3. Monogenetic causes of ADHD

Monogenetic causes refers to genes in which certain gene variants can trigger disorders that are associated with ADHD symptoms.
In rare cases, a single genetic defect can lead to ADHD.¹

As a gene can have various mutations, which (in the case of protein-coding genes) can cause a wide range of changes in protein activity (no protein activity at all, slightly reduced, normal, slightly increased, greatly increased…), monogenetic diseases can also occur in different forms or manifestations. Therefore, not every gene mutation of one of the genes mentioned here causes ADHD. We have included genes with a significantly increased prevalence of ADHD in certain variants as a monogenetic cause of ADHD. The numbers in brackets indicate the prevalence of ADHD in certain gene variants of the named gene. Some of the figures should be viewed with caution due to the very small number of people affected.

In addition to the genes listed here, there are several animal models in which a single gene has been deactivated and which develop ADHD symptoms (up to full-blown ADHD) as a result. These genes also represent monogenetic causes of ADHD.
Many monogenetic disorders are rare (orphan) diseases. Around 8000 rare diseases are currently known. ICD-10 has only listed around 500 of these as separate codes. ICD 11 will go much further here.²

The gene candidates mentioned below only very rarely appear as dysfunctional gene variants. ADHD is generally not considered to be a monogenetic disorder. However, we believe it is quite possible that monogenetic causes could explain a relevant proportion of ADHD cases.

The percentages in the headings indicate the prevalence of ADHD among people with ADHD of the respective dysfunctional gene variant.

• 1. FMR1 (fragile X syndrome, FXS) (full mutation: 42 to 59 %; premutation: 93 %)
• 2. CAPRIN1, Cell Cycle Associated Protein 1 (82 %)
• 3. PHF21A, PHD Finger Protein 21A (78 %)
• 4. Sex chromosome aneuploidy: 48,XXY; 48,XXX; 48,XYY and 48,XXYY (up to 72%)
• 5. CHD2, Chromodomain Helicase DNA Binding Protein 2 (65 %)
• 6. SETBP1 haploinsufficiency (65 %)
• 7. Klinefelter syndrome (47,XXY) (63 %)
• 8. DYRK1A, dual-specificity tyrosine phosphorylation-regulated kinase 1A (62 %)
• 9. TSC1, TSC Complex Subunit 1 (30 to 60 %)
• 10. ANK3, ANKYRIN 3 (57 %)
• 11. Trisomy 21, Down syndrome (14.6 % to over 50 %)
• 12. THRB, thyroid hormone β receptor gene (50 %)
• 13. CHD8-NDD (approx. 50 %)
• 14. SHANK2 (50 %)
• 15. 22Q11.2 Duplication syndrome (18.2 % to 44 %)
• 16. ANKRD11, Ankyrin Repeat Domain Containing 11 (KBG syndrome; 24% to 41%)
• 17. PAH (phenylketonuria, PKU; 40 %)
• 18. 22Q11.2 deletion syndrome (6 % to 37 %)
• 19. SRRM2, Serine/Arginine Repetitive Matrix 2 (36 % ?)
• 20. Velocardiofacial syndrome (22q11DS) (33 % ?)
• 21. NF1 (neurofibromatosis type 1; 28.9 %)
• 22. MBOAT7 encephalopathy (26.6 % ?)
• 23. BSN, Bassoon (25 %)
• 24. Cerebral folate transporter deficiency, FOLR1 (22.2 % ?)
• 25. CFTR, gene of the ciliary neurotrophic factor receptor, CNFTR (cystic fibrosis, cystic fibrosis; 5.26 % to 21.9 %)
• 26. NSD1, Sotos syndrome (21 %)
• 27. NRXN1 Exonic deletion (10 to 20 %)
• 28. ANKRD17, Ankyrin Repeat Domain Containing 17
• 29. KMT2B, lysine methyltransferase 2B
• 30. H1-4 (Rahman syndrome)
• 31. SATB2
• 32. ODC1, ornithine decarboxylase 1 (Bachmann-Bupp syndrome, BABS)
• 33. CYP27A1 (cerebrotendinous xanthomatosis, CTX)
• 34. SMAD4, Myhre
• 35. SETD5
• 36. RUNX1T1
• 37. Congenital disorder of glycosylation, CDG
  • 37.1. Transferrin, TF
  • 37.2. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A
  • 37.3. COG6
• 38. Monogenetic animal models for ADHD symptoms
  • 38.1. Monogenetic causes of hyperactivity
  • 38.2. Monogenetic causes of hyperactivity and hypoactivity
  • 38.3. Monogenetic causes of impulsivity
  • 38.4. Monogenetic causes of attention problems

1. FMR1 (fragile X syndrome, FXS) (full mutation: 42 to 59 %; premutation: 93 %)¶

The prevalence of fragile X syndrome is:

• Full mutation
  • 1 in 3,600 to 1 in 4,000 for men and approx. 1 in 4,000 to 1 in 6,000 for women³
  • 1 in 7,140 men and 1 in 11,000 women⁴
• Premutation
  • 1 in 855 for men and 1 in 291 for women⁴

Fragile X syndrome is the most common inherited cause of mental disability after trisomy 21 (Down syndrome).³

Fragile X syndrome (FXS) is caused by a full mutational expansion (>200 CGG repeats) in the FMR1 gene, resulting in a deficiency of the fragile X mental retardation protein (FRMP).⁵ Although most individuals with the premutation (55-200 CGG repeats) are considered unaffected by FXS, recent case studies have documented children with the premutation exhibiting cognitive deficits, behavioral problems, and/or autism spectrum disorders. ⁵
Fragile X syndrome is considered a monogenetic cause of ASD.
The incidence of ADHD and mental retardation is also increased⁶
ADHD prevalence:

• 54 to 59 % in a study of 63 boys with the full mutation⁷
• 42 % in a study on n = 31 boys⁸
• 93 % showed ADHD symptoms (out of 43 boys with the premutation). 79% showed ASD symptoms. The carriers of the premutation showed developmental problems, especially those who had clinical behavioral problems⁵

One study found no correlation between the FMR1 premutation and ADHD or anxiety in women.⁹

2. CAPRIN1, Cell Cycle Associated Protein 1 (82 %)¶

Prevalence: Only 15 people appear to have been found with CAPRIN1 haploinsufficiency so far.

Other names: Caprin-1; RNG105; GPI-Anchored Membrane Protein 1; GPIAP1; M11S1; Cytoplasmic Activation- And Proliferation-Associated Protein 1; Cytoplasmic Activation/Proliferation-Associated Protein-1; Membrane Component Chromosome 11 Surface Marker 1; GPI-Anchored Protein P137; RNA Granule Protein 105; GPI-P137; GPIP137; P137GPI; Membrane Component, Chromosome 11, Surface Marker 1; Activation/Proliferation-Associated Protein 1; Cell Cycle-Associated Protein 1; Caprin 1; GRIP137

The protein CAPRIN1 enables RNA-binding activity. CAPRIN1 may be involved in the negative regulation of translation and the positive regulation of dendritic spine morphogenesis. CAPRIN1 is located in the leading edge of the cell and in the cytosol.
CAPRIN1 is associated with

• Moyamoya angiopathy

Related paths:

• RNA binding
• RNA binding

Paralog: CAPRIN2

CAPRIN1 can regulate the transport and translation of mRNAs of proteins involved in synaptic plasticity in neurons and cell proliferation and migration in different cell types. CAPRIN1 binds directly and selectively to MYC and CCND2 RNAs. CAPRIN1 binds directly to several mRNAs associated with RNA granules in neuronal cells, including BDNF, CAMK2A, CREB1, MAP2, NTRK2 mRNAs as well as GRIN1 and KPNB1 mRNAs, but not to rRNAs.¹⁰

Haploinsufficiency of the CAPRIN1 gene is an autosomal dominant disorder associated with loss-of-function variants in cell cycle-associated protein 1 (CAPRIN1).
The CAPRIN1 protein regulates the transport and translation of neuronal mRNAs that are crucial for synaptic plasticity, as well as mRNAs encoding proteins that are important for cell proliferation and migration in different cell types.
CAPRIN1 variants with loss of function were associated with the following symptoms:¹¹

• Speech impediment/speech delay (100 %)
• mental disability (83 %)
• ADHD (82 %)
• ASS (67 %)
• Breathing problems (50 %)
• Anomalies of the limbs and skeleton (50%)
• Developmental delays (42%)
• Feeding problems (33 %)
• Seizures (33 %)
• Eye problems (33 %)

3. PHF21A, PHD Finger Protein 21A (78 %)¶

The prevalence of PHF21A dysfunction is unknown. Only around 20 cases have been reported to date. Unverifiable reports speak of a frequency of 1 in 1,100,000.

Other names: BHC80; KIAA1696; BM-006; BRAF35-HDAC Complex Protein BHC80; BHC80a; BRAF35/HDAC2 Complex (80 KDa); IDDBCS; NEDMS

The PHF21A gene encodes the protein BHC80, which is a component of the BHC complex. The BHC complex mediates the repression of neuron-specific genes in non-neuronal cells by cis-regulatory element (repressor element-1, RE1; neural restrictive silencer, NRS, NRSE). The BHC complex is recruited by REST to RE1/NRSE sites and acts as a chromatin modifier by deacetylation and demethylation of specific sites on histones. In the BHC complex, BHC80 can act as a scaffold. BHC80 inhibits KDM1A-mediated demethylation of ‘Lys-4’ of histone H3 in vitro, suggesting a role in the regulation of demethylation.¹²

PHF21A is associated with:¹³

• Intellectual developmental disorder with behavioral abnormalities
  • heavy (37.5 %)
  • moderate (25 %)
  • mild (37.5 %)
• craniofacial dysmorphism with or without seizures
• Potocki-Shaffer syndrome
• epileptic phenotype (58.33 %)
• Developmental and epileptic encephalopathy (DEE) (71.42 %)
  • Of the 5 patients with DEE, three developed infantile epileptic seizure syndrome (IESS)
  • The seizures of 2 patients (2/5, 40%) could be controlled with anti-seizure medication
• Overgrowth (100 % of 12 known people with ADHD)
• ADHD (77.78 % of 12 known persons with ADHD){Chen H, Chen Y, Wu H, Qiu X, Yu X, Wang R, Zhong J, Peng J (2023): De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review. Seizure. 2023 Oct;111:138-146. doi: 10.1016/j.seizure.2023.08.009. PMID: 37633153.}}, (4 out of 5 persons with ADHD for whom information on ADHD was available = 80%)¹⁴
• Hypotension (70 %)
• ASD (50 % % of 12 known persons with ADHD){Chen H, Chen Y, Wu H, Qiu X, Yu X, Wang R, Zhong J, Peng J (2023): De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review. Seizure. 2023 Oct;111:138-146. doi: 10.1016/j.seizure.2023.08.009. PMID: 37633153.}}, (3 of 6 persons with ADHD for whom information on ADHD was available = 80 %)¹⁴
• Sleep disorders (33.33 %)

Related metabolic pathways:

• Infectious diseases
• Chromatin organization

Paralog: PHF21B

4. Sex chromosome aneuploidy: 48,XXY; 48,XXX; 48,XYY and 48,XXYY (up to 72%)¶

Rare sex chromosome aneuploidy (SCA) disorder
Prevalence 48,XXYY: 1 in 18,000 to 40,000 male newborns¹⁵

Symptoms:

• tall stature (average height over 1.90 m)
• hypergonadotropic hypogonadism (testosterone deficiency)
• Infertility
• Developmental delays
• Learning disorders
• mental impairments

Common accompanying behavioral problems are

• ADHD (72%; for comparison: 36% for XXY, 52% for XXX and 76% for XYY)¹⁶¹⁷
• States of anxiety
• Depression
• Sleep disorders
• Irritability
• aggressive behavior

One study found:¹⁵
71% (of 101, 4.5 to 38 years) received psychotropic drugs, most commonly ADHD stimulants (78.9%, first medication success rate 43.9%), anti-anxiety/antidepressant medications (60.6%, first medication success rate 84.2%). Subsequent trials with medications of the same class improved the success rates per person in all medication classes except for sleep and mood stabilizers.

Assuming an ADHD prevalence of 50% across all variants and an aneuploidy prevalence of 1 in 30,000, this could explain one in 60,000 cases of ADHD in males. With an ADHD prevalence of 5 %

5. CHD2, Chromodomain Helicase DNA Binding Protein 2 (65 %)¶

Other names: Chromodomain Helicase DNA Binding Protein 2; ATP-Dependent Helicase CHD2; DKFZp686E01200 2; DKFZp547I1315; DKFZp781D1727; FLJ38614; CHD-2; EC 3.6.4.12; EC 3.6.1; DEE94; EEOC
The prevalence of CHD2 dysfunction is unknown. Only around 225 cases have been reported to date.

The CHD2 gene encodes an ATP-dependent enzyme that is involved in chromatin remodeling.
Pathogenic variants in CHD2 are very rare (orphan). There are 225 known diagnosed patients from 28 countries with various allelic variants in CHD2, including small intragenic deletions/insertions as well as missense, nonsense and splice site variants.¹⁸

65% (11 of 17) of the people with ADHD affected by CDH2 gene mutations showed ADHD, 57% ASD.¹⁸

6. SETBP1 haploinsufficiency (65 %)¶

The prevalence of SETBP1 haploinsufficiency is unknown. Only around 34 cases have been reported to date¹⁹

All individuals with SETBP1 haploinsufficiency syndrome (SETBP1-HD) or SETBP1-related disorders (SETBP1-RD) had neurological impairments, including intellectual disability/developmental delay (IDD), attention-deficit/hyperactivity disorder, autism spectrum disorder and/or seizures, and speech and language delays.²⁰
In SETBP1 haploinsufficiency syndrome, the following was found

• ADHD at 65 %
• ASD in 21 %, 75 % of whom also had comorbid ADHD

7. Klinefelter syndrome (47,XXY) (63 %)¶

The prevalence of Klinefelter in boys is 1 to 2 in 1,000. Only about a quarter of people with ADHD are diagnosed, as the effects are often mild.

Klinefelter syndrome is characterized by an additional X chromosome. 63% of people with ADHD, 65% with speech disorders and 27% with ASD.²¹.
Boys with Klinefelter without ADHD showed executive functions similar to those of boys with Klinefelter and ADHD. Apparently, Klinefelter itself is associated with executive problems.²²

8. DYRK1A, dual-specificity tyrosine phosphorylation-regulated kinase 1A (62 %)¶

The prevalence of DYRK1A dysfunction is very low and is said to be less than 1 in 1,100,000.

DYRK1A syndrome is a form of intellectual disability.
One study found evidence of ADHD in 18 out of 29 people with ADHD (62%)²³

Common symptoms of DYRK1A syndrome are:

• Mental disability
• Delayed speech development
• Motor problems
• Microcephaly (small head)
• Feeding problems
• Eye problems
• Behavioral problems
• Seizures
• Reduced height growth
• Autism symptoms

9. TSC1, TSC Complex Subunit 1 (30 to 60 %)¶

Other names: TSC Complex Subunit 1; Hamartin; KIAA0243; LAM; TSC; Tuberous Sclerosis 1 Protein; Tuberous Sclerosis 1, TSC-1
The prevalence of TSC1 dysfunctions is between 1:30,00 and 1:6,000.

TSC1 is probably a tumor suppressor gene that encodes the growth-inhibiting protein hamartin. Hamartin interacts with the GTPase-activating protein tuberin and stabilizes it. This hamartin-tuberin complex inhibits mTORC1 (Mammalian target of rapamycin complex 1) signaling, which is an important regulator of anabolic cell growth. Hamartin also acts as a co-chaperone for Hsp90, inhibiting its ATPase activity. Hamartin facilitates Hsp90-mediated folding of kinase and non-kinase clients, including TSC2, thereby preventing their ubiquitination and proteasomal degradation. TSC1 is involved in microtubule-mediated protein transport, but this appears to be due to unregulated mTOR signaling. TSC1 acts as a co-chaperone for HSP90AA1 and facilitates HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1. It increases ATP binding to HSP90AA1 and inhibits the ATPase activity of HSP90AA1. TSC1 competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, resulting in a reciprocal regulatory mechanism for the chaperoning of client proteins. TSC1 recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and the ubiquitin ligase HERC1.²⁴

Tsc1-mTORC1 signaling controls striatal dopamine release And cognitive flexibility.²⁵

TSC1 is associated with

• tuberous sclerosis
• Lymphangioleiomyomatosis

Related signal paths:

• MTOR signaling
• Gene expression (transcription)

Tuberous sclerosis is associated with ADHD²⁶²⁷ in 30 to 60 % of people with ADHD and with neuropsychiatric manifestations such as ADHD, ASD or mental retardation in 90 %.²⁸
The Austrian Tuberous Sclerosis Association offers the TAND checklist for tuberous sclerosis on.

TSC2-KO mice also show tuberosclerosis-associated neuropsychiatric disorders and epilepsy. TSC2-KO mice showed more severe expressions of hyperactivity and cognitive disorders in females. TSC-associated disorders are thought to be caused by hyperactivation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1). mTORC1 inhibitors ameliorate almost all TSC symptoms. The mTORC1 inhibitor sirolimus ameliorated TSC-associated neuropsychiatric disorders in TSC2-KO mice by modulating brain steroid levels and regulating E2/ERα-dependent transcriptional activation. Potentially, sirolimus could be useful for the treatment of TSC-associated neuropsychiatric disorders as well as diseases caused by sex differences and steroid levels.²⁹

10. ANK3, ANKYRIN 3 (57 %)¶

Other names: Ankyrin 3; Ankyrin 3, Node Of Ranvier (Ankyrin G); Ankyrin-G; Ankyrin-3; Ankyrin-3, Node Of Ranvier; ANKYRIN-G; MRT37; ANK-3

The prevalence of ANK3 dysfunction is extremely low. There are 5 known cases worldwide.³⁰

The scaffold protein ankyrin-3 differs immunologically from the ankyrins ANK1 and ANK2. It is found at the axonal initial section and at the nodes of Ranvier of neurons in the central and peripheral nervous system. Within the nodes of Ranvier, where action potentials are actively transmitted, ANK3 is an intermediate binding partner for neurofascin and voltage-gated sodium channels. ANK3 is required for the normal accumulation of voltage-gated sodium channels at the axon hillock and for the initiation of action potentials.³¹
In the human brain, ANK3 is found primarily in the cerebellum and, less densely, in the PFC, hippocampus, corpus callosum and hypothalamus. ANK3 plays a central role in regulating the localization of ion channels, membrane transporters, cell adhesion molecules and cytoskeletal proteins. ³²
There are connections between ANK3 and dopamine.³³³⁴ ANK3 is an essential component of AMPAR-mediated synaptic transmission and maintenance of spine morphology. ANK3 promotes the stability of somatodendritic GABA-ergic synapses in vitro and in vivo by counteracting the endocytosis of GABAA receptors.³⁵
ANK3 is expressed by oligodendrocytes, although it is found on the glial rather than the axonal side of the nodes.³⁶ ANK3 regulates the β-catenin/Wnt signaling pathway, which plays a role in bipolar Disorder.³⁷ A short ANK3 isoform is localized in dendritic spines and regulates NMDA receptor-dependent plasticity.³⁸ ANK3 accumulates in dendritic spines after chronic lithium treatment.³⁹ In bipolar Disorder, ANK3 mRNA is increased in the blood, although no increased expression was found in the brain.⁴⁰

ANK3 and stress
Prenatal stress influences the interaction of the ANK3 protein with PSD95. ANK3 appears to influence the effects of early childhood stress on the development of psychiatric disorders.⁴¹
Heterozygous ANK3+/- mice and mice in which ANK3 was deactivated in the dentate gyrus showed⁴²

• reduced anxiety
  • reversible through chronic lithium administration
• increased reward motivation
  • reversible through chronic lithium administration
    Ank3+/- mice showed an increased sensitivity to chronic stress:
• increased susceptibility to depression-like behaviors
• elevated corticosterone levels

ANK3 is associated with

• PTSD⁴³
• Autism⁴⁴⁴⁵
• Brugada syndrome, a form of cardiac arrhythmia.
• bipolar Disorder
  • e.g. rs10994336, rs1938526 and rs9804190³²
• mental disability.

OMIM: ANK3, ANKYRIN 3

ANK3 is associated with ADHD.⁴⁶ A study found this gene to be one of the 51 most likely gene candidates for ADHD.⁴⁷

Among 27 persons with ADHD (16 with monoallelic and 11 with biallelic ANK3 variants), the phenotype was found to be more severe in biallelic variants. Phenotypically were:⁴⁸

• Speech delay (92 %)
• ASS (76 %)
• mental disability (78 %)
• Hypotension (65 %)
• motor delay (68 %)
• ADHD (57%)
• Sleep disorders (50 %)
• Aggressiveness/self-harm (37.5 %)
• Epilepsy (35 %)
• Ataxia (11%, all with biallelic variants)

Most monoallelic variants lead to a shortened protein. The biallelic variants are almost exclusively missense mutations.
The mono- and biallelic variants appear to be localized differently in the three different ankyrin G isoforms, suggesting isoform-specific pathological mechanisms.

11. Trisomy 21, Down syndrome (14.6 % to over 50 %)¶

The prevalence of Down syndrome is given as 1:750.

Down syndrome correlated with a 1.74-fold risk of ADHD (14.6% overall) and a 5.4-fold risk of ASD (6.38% overall).⁴⁹
In special institutions for children with Down syndrome, more than 50% are said to suffer from ADHD at the same time.⁵⁰
Down syndrome is also associated with an increased ASD prevalence of 39%⁵¹

Mosaic Down syndrome is characterized by trisomy 21, which is not present in all cells. Among the persons with ADHD, 2.08 % were found to have mosaicism.⁵²
People with mosaicism were more likely than those not affected to show

• ADHD (+ 26.5 %; 17.7 % compared to 14.0 %)
• ASS (+ 44.8 %; 13.9 % compared to 9.6 %)

12. THRB, thyroid hormone β receptor gene (50 %)¶

The prevalence of THRB resistance is estimated at 1:19,000 to 1:40,000.⁵³

A (rarely occurring) genetic dysregulation of the TH beta receptor can cause increased blood thyroxine levels due to resistance to thyroid hormone β. 50% of people with ADHD show ADHD symptoms.⁵⁴
There was evidence of increased connectivity between regions of the default mode network and the dlPFC as well as weaker connectivity of the lingual gyrus to the bilateral insula (salience network). The former is associated with attention problems in ADHD, the latter with reduced habituation to visual stimuli and increased distractibility in ADHD.

Both hypothyroidism and hyperthyroidism cause cognitive changes. Depending on the degree of hypothyroidism, the cognitive effects can range from mild impairment of memory and attention to complete dementia. Hyperthyroidism can also cause inattention and hyperarousal, among other cognitive deficits.⁵⁵⁵⁶

THRB encodes the thyroid receptor isoforms TRβ1 and TRβ2, the THRA gene encodes the thyroid receptor alpha, TRα1.
The pituitary hormone TSH (thyroid-stimulating hormone) stimulates the thyroid gland to produce thyroxine (T4; prohormone) and then triiodothyronine (T3). The thyroid hormones (T3 and T4) in the blood in turn regulate the pituitary release of TSH within the hypothalamic-pituitary-thyroid axis, which is mediated by the receptor isoform TRβ2.
In the case of resistance to thyroid hormone β, this negative feedback loop, which stabilizes the TH level in the blood, is disrupted. This leads to increased TH and unsuppressed, i.e. normal TSH levels.⁵⁴

13. CHD8-NDD (approx. 50 %)¶

CHD8-related intellectual disability-autism-macrocephaly-tall stature syndrome is very rare, with 1 in 1,100,000 cases,{{Orpha.net:

CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by⁵⁷

• general overgrowth
  • Macrocephaly (usually in infancy) (in approx. 80 %)
  • Tall stature (usually during puberty) (in approx. 80 %)
• Developmental delay/intellectual disability
  • most frequently speech and movement delays
  • if intellectual disability, usually only in the mild to moderate range
• Autism spectrum disorder (in approx. 75 to 80 %)
  - ADHD (in approx. 50 %)
• neuropsychiatric problems
• neurological problems
• Sleep disorders (approx. 67%)
  • delayed onset of sleep
  • frequent awakenings at night
• Gastrointestinal problems (approx. 66%)
  • Constipation with or without periods of diarrhea
• Hypotension (in approx. 30 %)
• Anxiety (for 29 %)
• Seizures (in approx. 10 to 15 %)
• Dystonia (rare)
• Chiari I malformation (rare)

14. SHANK2 (50 %)¶

SHANK2 is very rare.

A deletion or a pathogenic sequence variant of the SHANK2 gene causes a SHANK2 disorder. This is associated with ASD, mental retardation and developmental delays.
Among 10 people with ADHD were found:⁵⁸

• ASA at 90 % (0.2 % of all ASA cases⁵⁹ to 0.38 % of all ASA cases)⁶⁰
• ADHD at 50%
• mild to moderate developmental delays
• sensory hyperreactivity and search behavior were more pronounced than sensory hyporeactivity
• Hypotension
• recurrent ear infections
• gastrointestinal anomalies
• no similar dysmorphic facial features
• significantly higher adaptive functional capacity than with PMS

15. 22Q11.2 Duplication syndrome (18.2 % to 44 %)¶

Other names: DUP22Q11.2; Chromosome 22q11.2 Microduplication Syndrome⁶¹

The 22q11.2-duplication syndrome Occurs once in 1600 births.
22q11.2Dup is usually inherited from the parents.
The prevalence of ADHD at 22q11.2Dup is around 18.2% to 44%.⁶²
Among persons with ADHD, a 22q11.2Dup was found in 0.25 to 0.33%.

Other typical symptoms are

• Facial abnormalities
• congenital heart defects
• Immunodeficiencies
• Cleft palate
• Short stature
• Obesity
• Developmental delay

ADHD symptoms are treated according to the usual regimens. A low starting dosage with slow up-dosing is also recommended here.

16. ANKRD11, Ankyrin Repeat Domain Containing 11 (KBG syndrome; 24% to 41%)¶

Other names: ANCO1; ANCO-1; LZ16; T13; Ankyrin Repeat Domain-Containing Protein 11; Ankyrin Repeats Containing Cofactor 1; Ankyrin Repeat-Containing Cofactor 1; Ankyrin Repeat Domain 11; Nasopharyngeal Carcinoma Susceptibility Protein
ANKRD11 malfunctions are very rare. The prevalence is given as less than 1:1,000,000.

The ANKRD11 protein contains an ankryin repeat domain. ANKRD11 inhibits the ligand-dependent activation of transcription. ANKRD11 is a chromatin regulator that modulates histone acetylation and gene expression in neural progenitor cells. ANKRD11 can recruit histone deacetylases (HDACs) to the p160 coactivator/nuclear receptor complex to inhibit ligand-dependent transactivation. ANKRD11 plays a role in the proliferation and development of cortical neural progenitor cells. ANKRD11 can regulate bone homeostasis.⁶³
ANKRD11 is associated with:

• rare genetic intellectual disabilities
• KBG syndrome
  • KBG is a rare syndrome. Genetic variants in ankyrin repeat domain 11 (ANKRD11) and deletions in 16q24.3 can cause KBG syndrome. In a group of 25 people with ADHD, 24% were diagnosed with ADHD.⁶⁴
    KBG goes hand in hand with⁶⁵
    • Macrodontia
    • pronounced craniofacial features
    • Short stature
    • Skeletal anomalies
    • global developmental delay
    • Seizures
    • mental disability
    • Hearing loss and/or middle ear infection
    • Visual disturbances
    • Cryptorchidism
    • Cardiopathy
    • Feeding problems

A survey of 91 people with ADHD revealed prevalence rates of⁶⁶

• 48 % Anxiety disorders
• 44 % Autism
• 41 % ADHD
• 37 % Hearing problems
• 37 % High level of frustration
• 36 % Visual disturbances
• 31 % seizures, of which
  • 52 % were currently able to control them with medication or a ketogenic diet
  • 30 % had treatment-resistant seizures
  • 22 % no longer had any seizures
  • none of the people with recent seizures lived independently
• 31 % Misaligned teeth
• 29 % Gastrointestinal problems in adulthood
  • of which all constipation
  • of which 73 % reflux
• 29 % Scoliosis
• 28% had difficulty falling asleep, almost half of whom needed medication such as melatonin to fall asleep
• 27 % Lordosis or kyphosis
• 26 % Problems sleeping through the night
• 26 % Outbursts of anger
• 25 % Aggression towards themselves or others
• 23 % Gastrointestinal problems in childhood
• 22 % Enamel problems
• 21 % increased need for sleep
• 19 % Problems with the palate
• 19 % Caries
• 19 % had too many teeth
• 19 % Depression
• 18 % Mood swings
• 18 % Sensory search behavior
• 15 % Hip problems
• 15 % binge eating
• 12 % Compulsions
• 12 % Tics
• 12 % Heart valve problems
• 11 % reduced appetite or anorexia
• 11 % Sensory avoidance behavior
• 9 % Sudden falling asleep during the day
• 9 % High blood pressure
• 8 % Regression (loss of previously acquired skills)
• 8 % Keloid scars
• 8 % Arthritis
• 8 % abnormal wound healing
• 5 % Osteoporosis
• 5 % Sleep apnea
• 4 % Restless legs syndrome.
• 4 % sudden drop in activity
• 1 % Schizophrenia
• 1 % Borderline personality disorder

17. PAH (phenylketonuria, PKU; 40 %)¶

Other names; Følling’s disease, Fölling’s disease, phenylpyruvic acid oligophrenia, oligophrenia phenylpyruvica, hyperphenylalaninemia
Prevalence: 1 / 8,000 (0.0125 %)

Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism due to mutations in the phenylalanine hydroxylase gene). PKU leads to a significant excess of phenylalanine (hyperphenylalaninemia). As phenylalanine and tyrosine pass through the blood-brain barrier via the same transporters, and these transporters have a higher affinity for phenylalanine, too little tyrosine reaches the brain if there is an excess of phenylalanine in the blood. Tyrosine is a precursor for dopamine, from which noradrenaline and adrenaline are further produced. Excess phenylalanine in the blood therefore leads to a lack of dopamine, noradrenaline and adrenaline in the brain.⁶⁷In addition, excess phenylalanine causes changes in cerebral myelin and protein synthesis as well as reduced levels of serotonin in the brain.⁶⁸ ADHD and phenylketonuria therefore have the common feature of a dopamine deficiency ^{69 7071}

A meta-analysis found ADHD and hyperactivity in 40% of people with ADHD (meta-analysis, k = 8, n = 222).⁷² A small study found an ADHD rate of 38 %.⁷³
People with ADHD often show symptoms of ADHD, although the subtypes with hyperactivity seem to predominate.^7475697677

Treatment with sapropterin improved ADHD symptoms in a pharma-funded study in phenylketunorie.⁷⁸ One study also suggests BH4 treatment for ADHD, which is helpful for PKU.⁷¹

18. 22Q11.2 deletion syndrome (6 % to 37 %)¶

Other names: DEL22Q11.2; C22DELq11.2; C22DDELS⁷⁹

The 22q11.2-deletion syndrome Occurs once in 2150 births, making it the most common deletion syndrome.
22q11.2Del usually develops de novo, i.e. not as an inheritance of genetic traits from the parents.
The prevalence of ADHD in 22q11.2Del is around 6% to 37%.⁶²
Among people with ADHD, 0.14% were found to have 22q11.2Del.

DEL22Q11.2 is associated with

• Chromosome 22Q11.2 Deletion syndrome, distal
• Corneal staphyloma.

More than 85% of DEL22Q11.2 people with ADHD without an ADHD diagnosis reported ADHD symptoms.⁸⁰

ADHD symptoms are treated according to the usual regimens. A low starting dosage with slow up-dosing is also recommended here.

People with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders such as ADHD, schizophrenia, depression or intellectual disability.⁸¹

19. SRRM2, Serine/Arginine Repetitive Matrix 2 (36 % ?)¶

Other names: Serine/Arginine Repetitive Matrix 2; SRL300; KIAA0324; SRm300; Cwc21; Serine/Arginine-Rich Splicing Factor-Related Nuclear Matrix Protein Of 300; KDa; Tax-Responsive Enhancer Element-Binding Protein 803; Ser/Arg-Related Nuclear Matrix Protein Of 300 KDa; SR-Related Nuclear Matrix Protein Of 300 KDa; Serine/Arginine Repetitive Matrix Protein; Splicing Coactivator Subunit SRm300; 300 KDa Nuclear Matrix Antigen; TaxREB803; Testicular Secretory Protein Li 53; RNA Binding Protein; HSPC075; 300-KD; SRM300; CWF21
SRRM2 malfunctions very rare. Among 1000 people with developmental delay and intellectual disability, 2 were found to have this genetic disorder. Intellectual disability has a prevalence of 1.65%, developmental delay has a prevalence of 6.5%.

SRRM2 is a protein-coding gene. It enables C2H2 zinc finger domain binding activity and protein N-terminus binding activity. SRRM2 is found in the Cajal body and nuclear speck. SRRM2 is involved in mRNA splicing as part of the U2-type catalytic step 2 spliceosome and the precatalytic U2 spliceosome. SRRM2 is a biomarker for Parkinson’s disease.⁸²

SRRM2 is associated with:

• Status epilepticus
• Chondromalacia of Patella

Related signal paths:

• Processing of Capped Intron-Containing Pre-mRNA
• RNA binding
• C2H2 zinc finger domain binding

Paralog: MUC12

SRRM2 gene variants with loss of function show common clinical features:⁸³⁸⁴

• Developmental delay
  • to varying degrees
  • a connection with SRRM2 was found in 0.3% of all persons with ADHD
• ADHD
  • ADHD symptoms in 8 out of 22 people with ADHD⁸⁴
• Autism
• Macrocephaly
• Hypotension
• gastroesophageal reflux
• Overweight/obesity

20. Velocardiofacial syndrome (22q11DS) (33 % ?)¶

Other names: CATCH 22, Cayler cardiofacial syndrome, Di George syndrome, DiGeorge sequence, microdeletion 22q11.2, monosomy 22q11, Sedlackova syndrome, Sphrintzen syndrome, syndrome of conotruncal anomaly with facial dysmorphia, Takao syndrome

22q11.2 deletion syndrome (DS)⁸⁵

The prevalence of velocardiofacial syndrome is 1 - 5 / 10,000 (0.01 to 0.05 %)⁸⁶

One study found ADHD in 2 out of 6 people with ADHD.⁸⁷

21. NF1 (neurofibromatosis type 1; 28.9 %)¶

Other names: Von Recklinghausen’s disease, Recklinghausen’s disease, neurofibromatosis Recklinghausen, peripheral neurofibromatosis
With a prevalence of around 1:3500 (0.029 %), it is one of the most common hereditary neurological diseases. Neurofibromatosis type 1 shows malformations of the skin and the central nervous system. Neurofibromatoses are nerve tumors.

Diagnostic criteria for neurofibromatosis type 1 are at least 2 of the following symptoms:⁸⁸

• Six or more café-au-lait spots (CAL) > 5 mm in diameter prepubertal and > 15 mm postpubertal.
• Freckling in the armpit or groin region.
• Two or more neurofibromas of any type or one plexiform neurofibroma (PNF)
• Glioma of the visual pathway
• Two or more iris nodules identified by slit lamp examination or two or more choroidal abnormalities (CAs) detected as irregular bright nodules by optical coherence tomography (OCT) or near infrared imaging (NIR imaging).
• Specific bony lesions such as sphenoid dysplasia, anterolateral bowing of the tibia or pseudarthrosis of the long tubular bones.
• A heterozygous pathogenic (= disease-causing) NF1 variant with an allele frequency of 50 % in normal tissue such as leukocytes.

A meta-analysis (k = 70, n = 3,653) found that children with NF1 had more severe symptoms of⁸⁹ compared to unaffected children in the parent rating

• Inattention (Hedges g = 1.20)
• Hyperactivity/impulsivity symptoms (Hedges g = 0.85)
• combined ADHD symptoms (Hedges g = 1.02)

Larger Effect sizes for inattention and hyperactivity/impulsivity correlated with higher age and lower intelligence quotient (IQ).⁸⁹

NF1 children with ADHD and children with primary ADHD show similar deficits in attention and executive functions.
NF1 showed a slower reaction time and greater learning difficulties.⁹⁰

Among 128 persons with ADHD (53.1 % girls), 28.9 % (37/128) were found to have ADHD, including 20 ADHD-C, 15 ADHD-I and 2 ADHD-HI. ADHD and ASD occur more frequently in neurofibromatosis type 1 ⁹¹⁹²
Other comorbidities of neurofibromatosis type 1 were macrocephaly (head circumference more than 2 SDs above the age average, 37.5 %), headache (18.6 %), cognitive impairment (7.8 %), motor deficits (6.2 %) and epilepsy (4.68 %). MRI revealed T2-weighted hyperintensities in the basal ganglia and/or cerebellum (70.5 %), optic nerve gliomas (25.8 %), plexiform neurofibromas (9.3 %), Chiari malformation type 1 (6.7 %), arachnoid cysts (5 %), gliomas of the central nervous system (3.1 %).⁹³
In a survey, n = 109 parents of children with neurofibromatosis reported severe ASD in 29.4 %, moderate to mild ASD in 26.6 % and AuADHD in 26 % to 53.8 %.⁹⁴
One study found ADHD in 10.5% of NF1-berioffected individuals by 36 months of age.⁹⁵

In 5 to 11% of people with NF-1, this is due to a microdeletion syndrome of neurofibromatosis type 1.
In 57 persons with ADHD with NF-1 microdeletion syndrome:⁹⁶

• 28 people with ADHD type 1, 4 type 2, 2 type 3, 9 atypical deletions and 14 persons with undetermined deletions
• in 33 out of 41 (80.5 %) learning difficulties
• in 39 out of 49 (79.6 %) developmental delays
• expressive and/or receptive language delays in 35 of 49 (71.4 %)
• in 38 out of 56 (67.9 %) describable facial features
• in 23 of 42 (54.8 %) ADHD
• in 25 of 57 (43.8 %) plexiform neurofibromas
• in 3 of 57 (5.2 %) malignant peripheral nerve sheath tumors
• IQ decreased (between 50 and 96; 22 people with ADHD studied, 21 of whom were adults). Of the adults had:
  • 14 out of 21 (66.7 %) have a high school diploma
  • 4 out of 21 (19.0 %) had some college experience.

In NF-1, dopamine deficiency correlates with learning difficulties.⁹⁷ NF1 model mice showed reduced tyrosine hydroxylase expression in the striatum and VTA, 20% reduced dopamine levels in the hippocampus and 61% reduced DARPP32 phosphorylation. Postsynaptic D1 receptor expression in the hippocampus was unchanged. A D1 agonist was able to correct the resulting impairment of LTP.⁹⁷

22. MBOAT7 encephalopathy (26.6 % ?)¶

Out of 15 persons with ADHD encephalopathy, 4 showed attention problems (26.6%).⁹⁸
MBOAT7 encephalopathy is associated with neurodevelopmental disorders, mental retardation, epilepsy and neuropsychiatric disorders such as ADHD and ASD.

23. BSN, Bassoon (25 %)¶

The prevalence of BSN de novo variants is unknown.

Of 29 persons with ADHD with a de novo variant of BSN; which encodes the presynaptic protein bassoon, showed⁹⁹

• 49 % Epilepsy
• 38 % Developmental delay
• 34 % Obesity
• 28 % Speech delay
• **25 % ADHD **
• 17 % ASS

24. Cerebral folate transporter deficiency, FOLR1 (22.2 % ?)¶

Among 9 persons with ADHD found, 2 were found to have ADHD (22.2%).¹⁰⁰
The first abnormalities were febrile convulsions and ADHD symptoms. 44.4% suffered from ataxia and neuromotor and mental retardation,

25. CFTR, gene of the ciliary neurotrophic factor receptor, CNFTR (cystic fibrosis, cystic fibrosis; 5.26 % to 21.9 %)¶

Other names: CF Transmembrane Conductance Regulator; DJ760C5.1; TNR-CFTR; CFTR/MRP; ABC35; ABCC7; MRP7; Cystic Fibrosis Transmembrane Conductance Regulator; Channel Conductance-Controlling ATPase; CAMP-Dependent Chloride Channel; CF; Cystic Fibrosis Transmembrane Conductance Regulator, ATP-Binding Cassette (Sub-Family C, Member 7); Cystic Fibrosis Transmembrane Conductance Regulator (ATP-Binding Cassette Sub-Family C, Member 7); Cystic Fibrosis Transmembrane Conductance Regulating; ATP-Binding Cassette Sub-Family C, Member 7; ATP-Binding Cassette Sub-Family C Member 7; EC 3.6.3.49; EC 5.6.1.6; EC 3.6.3

A CFTR gene malfunction is said to be present in 3 to 4 % of the population, i.e. in every 25th to 33rd person.¹⁰¹ Cystic fibrosis affects one in every 3,300 to 4,800 newborns.

Cystic fibrosis is associated with increased ADHD symptoms.¹⁰² Reported prevalence rates of ADHD in pwCF ranged from 5.26% to 21.9%.¹⁰³

Cystic fibrosis correlates with mutations in the CFTR gene¹⁰⁴, which has been identified as a gene candidate for ADHD.^105102106
CTFR-KO zebrafish show ADHD symptoms such as hyperactivity, impulsivity and attention problems.¹⁰⁷

The protein CFTR encodes a member of the ATP-binding cassette transporter (ABC) superfamily. CFTR functions as a chloride channel, making it unique among members of this protein family, and controls the secretion and absorption of ions and water in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP binding by the nucleotide-binding domains and ATP hydrolysis. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a protein that is fixed on the surface of cells, a so-called chloride channel. Mutations in the CFTR gene in humans lead to the absence or impaired function of the channel, which can cause cystic fibrosis and congenital aplasia of the vas deferens (CAVD). CFTR is an epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport, fluid homeostasis (including airway homeostasis). CFTR mediates the transport of chloride ions across the cell membrane. Chloride channels are a family of anion-selective channels involved in a variety of biological processes, including regulation of neuronal, skeletal, cardiac and smooth muscle excitability, regulation of cell volume, transepithelial salt transport and acidification of intracellular and extracellular compartments. CFTR channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3)(-); the selectivity depends on the extracellular chloride concentration. CFTR also exerts its function by modulating the activity of other ion channels and transporters. CFTR contributes to the regulation of the pH and ionic content of the surface fluid layer of the airways and thus plays an important role in the defense against pathogens. CFTR modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex. CFTR inhibits the activity of the ENaC channel containing the subunits SCNN1A, SCNN1B and SCNN1G, as well as the activity of the ENaC channel containing the subunits SCNN1D, SCNN1B and SCNN1G, but not the ENaC channel containing the subunits SCNN1A, SCNN1B and SCNN1G. CFTR can regulate bicarbonate secretion and recycling in epithelial cells by regulating the transporter SLC4A7. CFTR can inhibit the chloride channel activity of ANO1. CFTR plays a role in chloride and bicarbonate homeostasis during epididymal maturation and capacitation of spermatozoa.¹⁰⁴
CFTR is associated with

• Cystic fibrosis
  • Cystic fibrosis correlates with increased L-dopa levels in blood and urine.¹⁰⁸ This is an indication of a link between cystic fibrosis and the dopamine balance. However, cystic fibrosis can have various genetic (co-)causes, so that a conclusion about CFTR is not necessarily given.
• Congenital bilateral aplasia of the vas deferens
• Cystic fibrosis
  • Cystic fibrosis is the most common fatal genetic Disorder in populations of Northern European descent.
  • The most common mutation in cystic fibrosis, DeltaF508, leads to impaired folding and transport of the encoded protein. Several pseudogenes have been identified in the human genome.

Related signal paths:

• wtCFTR
• delta508-CFTR traffic / generic scheme (standard and CF)
• IL-1 Family Signaling Pathways
• Enzyme binding
• PDZ domain binding

Paralog: ABCC4

OMIM: Gene of the ciliary neurotrophic factor receptor CNFTR

CFTR (CNFTR) is a candidate gene for ADHD.¹⁰⁵

26. NSD1, Sotos syndrome (21 %)¶

Sotos syndrome results from a malformation of the NSD1 gene and occurs de novo in 95% of cases. The prevalence is 1 in 14,000 births.

Symptoms:¹⁰⁹

• prenatal tall stature
• postnatal tall stature
• Macrosomia (weight of the child above the 95th percentile, 4350 g)
• excessive growth in the first 5 years of life, especially in the 2nd and 3rd year of life
• morphological bone age higher than the actual age
• muscular hypotension
• Dolichocephalus (longitudinal skull, excessive longitudinal growth of the skull)
• facial dysmorphia
• Hypertelorism
• little hair, receding hairline
• large forehead
• long, accentuated chin
• Orthopaedic problems (e.g. scoliosis, foot deformities)
• Developmental disorders (very different degrees)
  • motorized
  • cognitive
  • linguistic
• ASS: 28 %
• ADHD: 21 %¹¹⁰

27. NRXN1 Exonic deletion (10 to 20 %)¶

The prevalence of exonic NRXN1 deletions in the general Danish population was 0.07%, the prevalence of all NRXN1 deletions was 0.255%.¹¹¹
An English study found a prevalence of 0.039% and 0.07% respectively.¹¹²

Exonic NRXN1 deletions correlated with

• increased risk of ADHD:
  • 4.68 times the risk of ADHD¹¹³
  • 2.01 times the risk of ADHD¹¹¹

Based on an ADHD prevalence of 5 to 10 %, we assume an ADHD risk of 10 to 20 %.

Non-exonic deletions were not associated with a significantly increased risk of ADHD.¹¹¹

Exonic NRXN1 deletions were also associated with a massively increased risk of further psychiatric disorders:

• 20.3 times the Tourette’s risk¹¹⁴
• 9.91 times the risk of epilepsy¹¹⁵
• 8.14 times the risk of mental retardation / intellectual development disorder¹¹⁶
• 7.2-fold ASS risk¹¹⁷
• 3.05-fold ADHD risk¹¹¹
• Depression:
  • 2.01-fold risk of depression¹¹⁸
  • no significantly increased risk of schizophrenia¹¹¹
• no significantly increased risk of schizophrenia¹¹¹

28. ANKRD17, Ankyrin Repeat Domain Containing 17¶

Other names: Ankyrin Repeat Domain 17; GTAR; KIAA0697; NY-BR-16; MASK2; Serologically Defined Breast Cancer Antigen NY-BR-16; Ankyrin Repeat Domain-Containing Protein 17; Gene Trap Ankyrin Repeat Protein; FLJ22206; CAGS
So far, 33 people with ADHD have been identified worldwide.¹¹⁹

ANKRD17 is associated with:

• ANKRD17-related neurodevelopmental syndrome¹²⁰
  • Developmental delays, especially in speech
  • characterized by variable mental disability
  • Further features:
    • ASS
    • ADHD
    • ophthalmological anomalies (strabismus, refractive errors)
    • Growth disorders
    • Nutritional difficulties
    • recurrent infections
    • Gait and/or balance disorders
    • Epilepsy
  • Characteristic craniofacial features:
    • triangular face shape
    • high front hairline
    • deep-set and/or almond-shaped eyes with periorbital fullness
    • low-set ears
    • thick nostrils
    • flared nostrils
    • full cheeks
    • thin vermilion (vermilion) on the upper lip
    • rarer
      • Cleft palate with Pierre Robin sequence
      • Renal agenesis
      • Scoliosis.
• Chopra-Amiel-Gordon syndrome
• non-specific syndromic intellectual disabilities
• KBG syndrome
  • KBG is a rare syndrome. Genetic variants in ankyrin repeat domain 17 (ANKRD17), ANKDR 11 and deletions in 16q24.3 can cause KBG syndrome.
  • More on KBG syndrome under ANKRD11, Ankyrin Repeat Domain Containing 11

29. KMT2B, lysine methyltransferase 2B¶

Other names: MLL2; TRX2; HRX2; WBP7; MLL4; Histone-Lysine N-Methyltransferase 2B; KIAA0304; CXXC10; MLL1B; Myeloid/Lymphoid Or Mixed-Lineage Leukemia (Trithorax Homolog, Drosophila) 4; Myeloid/Lymphoid Or Mixed-Lineage Leukemia Protein 4; Lysine (K)-Specific Methyltransferase 2B; WBP-7; Histone-Lysine N-Methyltransferase MLL4; Mixed Lineage Leukemia Gene Homolog; Lysine N-Methyltransferase 2B; WW Domain Binding Protein 7; WW Domain-Binding Protein 7; Trithorax Homologue 2; Trithorax Homolog 2; EC 2.1.1.364; DYT28; MRD68

The KMT2B protein contains several domains, including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains and a SET domain (Suppressor of Variegation, Enhancer of Zeste, and Trithorax). The SET domain is a conserved C-terminal domain that is characteristic for proteins of the MLL (mixed-lineage leukemia) family. The KMT2B gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines.
KMT2B is a histone methyltransferase that catalyzes the methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of “Lys-4” of histone H3 (H3K4) via a non-processive mechanism. As part of the chromatin remodeling machinery, it predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair occur.KMT2B likely plays a redundant role with KMT2C in the accumulation of H3K4me1 marks on primed and active enhancer elements. KMT2B plays a central role in the regulation of beta-globin locus transcription by being recruited by NFE2. KMT2B plays an important role in controlling the amount of H3K4me during oocyte growth and pre-implantation development. KMT2B is required during the transcriptionally active period of oocyte growth for the establishment and/or maintenance of H3K4 trimethylation (H3K4me3), the global transcriptional silencing that precedes resumption of meiosis, oocyte survival and normal activation of the zygotic genome.¹²¹
KMT2B is associated with

• intellectual development disorder, autosomal dominant 68
• Tumor (possibly)
• Dystonia 28, onset in childhood
  KMT2B-Related Dystonia is associated with ADHD Symptoms.¹²²
  • Gene variants that can trigger the so-called “KMT2B-Related Dystonia” are:
    • heterozygous pathogenic variant in KMT2B or
    • heterozygous interstitial deletion of 19q13.12, which includes a KMTB2 whole gene deletion
  • KMT2B-Related Dystonia is a very rare Disorder. To date, 39 people with ADHD are known.
  • Onset of dystonia usually within the first ten years of life, but can also occur in the second decade or later
  • First appearance:
    • Mostly dystonia of the lower limb, manifested as:
      • Toe walk
      • abnormal gait
      • Balance disorders
    • Rarer:
      • Dystonia of the upper limbs
      • cervical or truncal dystonia
  • With increasing age:
    • pronounced cervical, laryngeal and/or cranial dystonia, manifested as
      • Retrocollis
      • Torticollis
      • Dysarthria/Anarthria
      • Dysphonia
      • Difficulty swallowing and chewing
  • Within two to 11 years after onset: development into generalized dystonia
  • KMT2B-Related Dystonia is associated with ADHD symptoms.

Related signal paths:

• PKMTs methylate histone lysines
• Gene expression (transcription)
• DNA-binding transcription factor activity
• Histone methyltransferase activity (H3-K4-specific)

Paralog: KMT2A

KMT2B-Related Dystonia is associated with ADHD symptoms.¹²²¹²³

30. H1-4 (Rahman syndrome)¶

Other names: H1.4 Linker Histone, Cluster Member; HIST1H1E; H1s-4; H1.4; H1F4; Histone Cluster 1 H1 Family Member E; H1 Histone Family, Member 4; Histone Cluster 1, H1e; Histone 1, H1e; Histone H1s-4; Histone H1.4; Histone H1b; H1e; DJ221C16.5; RMNS; H1E

H1-4 encodes a protein. The histone H1 protein binds to the linker DNA between the nucleosomes and forms the chromatin fiber. Histone H1 is necessary for the condensation of nucleosome chains into more highly structured fibers. It also acts as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation.¹²⁴

H1-4 is associated with

• Hist1h1e syndrome (Rahman syndrome)¹²⁵
  • Mental disability (mild to severe) (100 %)
  • Abnormal brain MRI (92%)
    • in particular anomalies of the corpus callosus
  • Cryptorchidism (75 %)
  • Hypotension (67 %)
  • Behavioral problems (59 %)
    • Anxiety, phobias
    • compulsive behavior
    • ADHD
    • Aggression
    • auditory hypersensitivity
    • ASS symptoms
  • Skeletal features (54 %)
  • Abnormal dentition (51 %)
    • Crumbling teeth
    • missing teeth
    • multiple caries
  • Congenital cardiac anomalies / Abnormal echocardiogram (40 %)
    • Atrial septal defect most common
  • Hypothyroidism (29 %)
  • delayed motor development

Related signal paths:

• cellular reactions to stimuli
• programmed cell death

Paralog: H1-5

31. SATB2¶

SATB2-associated syndrome (SAS) is a multisystem disorder with developmental delay or mental retardation.
Causes: de novo occurrence of:¹²⁶

• heterozygous intragenic pathogenic SATB2 variant
• heterozygous non-recurrent deletion at 2q33.1, which includes SATB2
• Chromosome translocation or inversion with a 2q33.1 breakpoint that disrupts SATB2
• chromosomal duplication with breakpoints that include SATB2.

Symptoms:¹²⁶

• Speech delay and/or lack of speech (in all people with ADHD)
• jovial or friendly personality
• autistic tendencies
  - Restlessness or aggressive outbursts
• Self-harm
  - Impulsiveness
  - Hyperactivity
• States of anxiety
• Difficulty falling asleep and staying asleep
• sensory problems
• Hypotension (in most people with ADHD)
• EEG abnormalities (frequent)
• clinical seizures (20% of people with ADHD)
• Status epilepticus during sleep
• non-specific dysmorphic features
• Palate anomalies (cleft palate, high arched palate, laryngeal insufficiency, bifid uvula)
• Dental anomalies (including abnormal shape or size of the upper central incisors, tooth protrusion, hypodontia and delayed tooth eruption)
• Skeletal anomalies (scoliosis, curvature of the tibia and joint contractures)
• Bone fractures (one in three)
• low bone mineral density (one in four)
• pre- and postnatal growth disorders
• Nutritional problems
• Eye anomalies (strabismus, refractive errors)
• cardiovascular, genitourinary and ectodermal findings

32. ODC1, ornithine decarboxylase 1 (Bachmann-Bupp syndrome, BABS)¶

Other names: ODC; Ornithine decarboxylase; EC 4.1.1.17; NEDBIA; NEDBA; BABS

The enzyme ODC1 catalyzes the first and rate-limiting step of polyamine biosynthesis, which converts ornithine to putrescine, which is the precursor for the polyamines spermidine and spermine. Polyamines are essential for cell proliferation and play a role in cellular processes ranging from DNA replication to apoptosis. The activity level of the ODC1 enzyme varies in response to growth-promoting stimuli and has a high turnover rate compared to other mammalian proteins. Originally, the gene encoding this enzyme was localized on both chromosome 2 and chromosome 7. It has since been found to be localized on 2p25, with a pseudogene located on 7q31-qter.¹²⁷
ODC1 is associated with:

• Sleeping sickness
• Bachmann-Bupp syndrome
  • Bachmann-Bupp syndrome (BABS) is characterized by¹²⁸
    • pronounced alopecia (hair loss)
    • global developmental delay in the moderate to severe range
    • Hypotension
    • non-specific dysmorphic features
    • Behavioral problems
      • ASS
        - ADHD
    • Feeding problems
    • Hair
      • pronounced alopecia (hairlessness)
      • usually present at birth
      • can be sparse
      • may have unexpected color
      • falls out in large clusters in the first weeks of life
    • Seizures at the beginning of later childhood (rare)
    • Conductive hearing loss (rare)

Abnormal metabolites of polyamine metabolism (including elevated levels of N-acetylputrescine) are indicative of BABS.
Diagnosis by molecular genetic testing for heterozygous pathogenic de novo variants of the ODC1 gene.

Related signaling pathways:

• L-methionine salvage cycle III
• Regulation of activated PAH-2p34 by proteasome-mediated degradation
• Protein homodimerization activity
• Ornithine decarboxylase activity

Paralog: AZIN2

33. CYP27A1 (cerebrotendinous xanthomatosis, CTX)¶

Cerebrotendinous xanthomatosis is a rare genetic disorder (prevalence 1:70,000) of the CYP27A1 gene that is inherited in an autosomal recessive manner. CTX is often only diagnosed in early adulthood due to the neurological symptoms that then become apparent.¹²⁹
CTX includes:¹³⁰

• Lipid storage impaired
• Bile acid biosynthesis pathways altered
• Cholesterol metabolites (e.g. cholestanol) increased in
  • Fabric
  • Brain
  • Eye lens
  • Tendons

Symptoms:¹³⁰

• progressive neurological problems (64-92%)
  • Spasticity
  • Pyramidal signs
• neuropsychiatric symptoms
  • cognitive impairments (87 %)
  • Behavioral disorders
• juvenile cataracts (82 %)
• Xanthomas (yellowish / orange fat deposits)
  • Tendon xanthomas (76 %)
• Osteoporosis (65 %)
• chronic diarrhea (31 %)
• psychiatric disorders (11.4%)
• Cardiovascular diseases

Cerebrotendinous xanthomatosis may be associated with ADHD symptoms.¹³¹¹³⁰

34. SMAD4, Myhre¶

Other names: SMAD Family Member 4; DPC4; MADH4; Mothers Against Decapentaplegic Homolog 4; Deletion Target In Pancreatic Carcinoma 4; MAD Homolog 4; MAD, Mothers Against Decapentaplegic Homolog 4 (Drosophila); Mothers Against Decapentaplegic, Drosophila, Homolog Of, 4; SMAD, Mothers Against DPP Homolog 4 (Drosophila); Deleted In Pancreatic Carcinoma Locus 4; SMAD, Mothers Against DPP Homolog 4; Mothers Against DPP Homolog 4; SMAD 4; HSMAD4; MYHRS; Smad4; JIP¹³²

Associated with:

• Myhre syndrome
  • Since its discovery in 1981, only 300 cases of Myhre have been detected worldwide¹³³
• juvenile polyposis syndrome

Connected signal paths:

• Autolysis of the E3 ubiquitin ligase COP1
• Gene expression (transcription)
• DNA-binding transcription factor activity
• sequence-specific DNA binding

Paralog: SMAD2

Myhre is associated with an increased prevalence of ADHD and ASD.¹³³

Symptoms of Myhre syndrome:¹³³

• Joint stiffness
• restrictive lung and cardiovascular diseases
• progressive and proliferative fibrosis
• Skin thickening
• recurrent infections (including otitis media, sinusitis, mastoiditis, croup)
• Hearing loss (progressive)
• Growth impaired early on
• Obesity in adolescence
• Refractive error
• Astigmatism
• Correctopia
• Abnormalities of the optic nerve
• gastroesophageal reflux disease
• Constipation
• Encopresis
• Stenosis of the GI tract (less common)
• Hirschsprung’s disease (less common)
• metabolic dysfunction of the liver (less common)

Traumas can be triggering:¹³³

• abnormal scarring
• Adhesions
• invasive medical interventions / operations
• Effusions in the heart, airways, lungs, uterus or peritoneum, which can develop into fibrosis

Characteristic facial features in most people with ADHD:¹³³

• short palpebral fissures
• deep-set eyes
• Underdevelopment of the upper jaw
• short philtrum
• thin upper lip
• narrow mouth
• Prognathy

Neurological symptoms:¹³³

• Developmental delays (usually mild to moderate)
• cognitive impairments (usually mild to moderate)
• ASS
• ADHD
• Fear

35. SETD5¶

Cause pathogenic gene variants of SETD5:¹³⁴

• Hypotension (39.2 %)
• hyperkinetic movement disorders including stereotypies and chorea (21.4%)
• Gait disorders (35.7 %)
  • Toe walking
  • unsteady gait
  • Changes in fine motor skills
• Epilepsy (14 %)
  • epileptic spasms
  • focal motor and non-motor seizures
• mild to severe intellectual disability or global developmental delay (75%)
• borderline intellectual capacity (21.4 %)
• ASS
• ADHD
• psychotic disorders
• other internalizing and externalizing symptoms

36. RUNX1T1¶

Runt-related transcription factor 1 translocated to 1 (RUNX1T1; also known as Eight-Twenty-One [ETO]) encodes a transcriptional regulator for hematopoietic genes and is known to be involved in hematologic malignancies, particularly acute myeloid leukemia (AML).
RUNX1T1 de novo changes:¹³⁵

• craniofacial dysmorphia
• neurological developmental disorders, including
  • Developmental delays
  • Learning disorders
  • ADHD
  • ASS

37. Congenital disorder of glycosylation, CDG¶

To date, there have only been a few cases in which abnormal glycosylation (congenital disorder of glycosylation, CDG) has been associated with ADHD:¹³⁶

• Alpha-1,3-glucosyltransferase (ALG8) CDG shows musculoskeletal, dermatologic and cardiac symptoms as well as mental retardation¹³⁷
• People with ADHD showed
• increased biantennary glycans with antenna fucose (A2FG2) and decreased tri- and tetra-antennary glycans.¹³⁸¹³⁹
• reduced α2-3 sialylation¹³⁹
• A single case with conserved oligomeric Golgi (COG-) CDG showed ADHD.¹⁴⁰

CDG has already been described in other neurodevelopmental disorders such as autism.
Other N-glycosylation abnormalities have been described in ADHD. The following were found in people with ADHD

A connection was also found with ASD, ataxia and other disorders that occur more frequently with ADHD,¹⁴¹

A lack of N-linked glycosylation can affect the membrane localization of the D5R (but not the D1R)¹⁴². The D5R plays a role in ADHD.
Conflicting glycosylation of the dopamine transporter (DAT) leads to more efficient transport of dopamine (which is the classic pathway for ADHD) and is discussed as a possible pathway for midbrain dopamine cell vulnerability in Parkinson’s disease.¹⁴³

37.1. Transferrin, TF¶

A case study reports on a young woman with a heterozygous transferrin mutation c.1295 A > G, which destroys the glycosylation site on asparagine 432. This means that the transferrin of the person with ADHD only has a single glycosylation site, and hypoglycosylation is not indicative of CDG disease. ADHD was present.¹³⁶ MPH led to side effects, while lisdexamfetamine resolved ADHD symptoms without side effects. The case study suggests a monogenetic cause possibility due to transferrin mutations for ADHD.

37.2. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A¶

Other names: STT3-A, TMC, Integral Membrane Protein 1, ITM1, Dolichyl-Diphosphooligosaccharide-Protein Glycosyltransferase Subunit STT3A, STT3A, Catalytic Subunit Of The Oligosaccharyltransferase Complex, Dolichyl-Diphosphooligosaccharide Protein Glycotransferase, Oligosaccharyl Transferase Subunit STT3A, Transmembrane Protein TMC

The protein STT3A is a catalytic subunit of the N-oligosaccharyltransferase (OST) complex, which transfers glycan chains to asparagine residues of target proteins in the endoplasmic reticulum. It is associated with CFTR activation by S-nitrosoglutathione (normal and CF) and the translation of structural proteins.
STT3A is associated with

• congenital disorder of glycosylation, type Iw, autosomal recessive
• congenital disorder of glycosylation, type Iw, autosomal dominant

In view of the influence of STT3A on N-glycolysis, we assume that the pathway of action on the dopaminergic system is comparable to that of 1.105. MAN2A2.

One study found STT3A to be one of the 51 most likely gene candidates for ADHD.⁴⁷

Autosomal dominant congenital glycosylation disorder (CDG) type Iw (OMIM# 619714) Is caused by a heterozygous mutation in the STT3A gene. Most CDGs are inherited in an autosomal recessive (AR) manner, but several cases with an autosomal dominant (AD) form of AR-CDG have recently been identified.
A case study describes a 17-year-old male with macrocephaly, failure to thrive, short stature, epilepsy, ASD, ADHD, mild developmental delay, intermittent hypotonia, dysmorphic features, and a slightly enlarged aortic root with a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser). This variant removes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The metabolomic profile indicates an abnormal CDG type Iw transferrin profile. Phenotypic, molecular and metabolic findings were consistent with CDG type Iw due to a heterozygous STT3A variant.¹⁴⁴

37.3. COG6¶

Two Swedish cases of congenital glycosylation disorders of the conserved oligomeric Golgi complex subunit 6 (COG6-CDG) are known.
One of them was diagnosed with ADHD at the age of 4 years and 9 months. The other was not (yet) diagnosed with ADHD at the age of 3.5 years.
Other clinical symptoms included mental retardation, delayed myelination of the brain, progressive microcephaly, joint laxity, hyperkeratosis, frequent infections and tooth enamel hypoplasia. Compound heterozygous variants in COG6 were identified in one family: c.785A>G; p.Tyr262Cys and c.238G>A; p.Glu80Lys. In addition, a previously undescribed homozygous duplication (c.1793_1795dup) was considered to be the cause of the disease. The cells of persons with ADHD show significantly slower anterograde and retrograde ER-Golgi transport.¹⁴⁰

38. Monogenetic animal models for ADHD symptoms¶

Animal models are used to investigate the effects of individual deactivated or overexpressed genes. Since in the vast majority of cases only a single gene is altered, the effects of this single gene can be easily determined by comparison with the same mouse strain without gene alteration.
Cabana-Domínguez et al have compiled an overview of 161 mouse models in which the manipulation of individual genes triggered hyperactivity, hyper- and hypoactivity, impulsivity or inattention.¹⁴⁵

38.1. Monogenetic causes of hyperactivity¶

Cabana-Domínguez et al found 146 mouse models in which the manipulation of the following genes triggered hyperactivity:¹⁴⁵

• ABCA2
• ABCG1
• ACTL6B
• ADCY3
• ADCYAP1
• ADIPOR2
• ANKFN1
• ANKS1B
• AP3B2
• AP3B2
• AP3D1
• APAF1
• APP
• ARRDC3
• ARSA
• ATF2
• ATP1A3
• ATRN
• BDNF
• CACNA2D3
• CACNA2D4
• CACNG2
• CADM1
• CALM1
• CAMK2A
• CDH23
• CDK17
• CDK5R1
• CDKL5
• CELF4
• CHD3
• CHD7
• CHRD
• CHRM1
• CHRM4
• CIC
• CKAP5
• CLIC5
• CNTNAP2
• CREBBP
• DGAT1
• DGKB
• DISC1
• DNAJB5
• DRD1
• DRD2
• DRD3
• DTNBP1
• DUSP18
• EEF1B2
• ELMOD3
• EN2
• EPS15L1
• ESPN
• ESR1
• FMR1
• FOS
• FOXI1
• FXR2
• GABRA1
• GABRA3
• GABRB3
• GIT1
• GLRA1
• GNAI2
• GNAO1
• GPR135
• GPR88
• GRIA1
• GRID2
• GRIN2B
• HMOX1
• HTR2C
• HTT
• IGSF9B
• IL6
• INTS3
• KCNA4
• KCNE1
• LDLR
• LMX1A
• LRRK2
• MAGI2
• MAOB
• MAPK3
• MAPT
• MCOLN3
• MYO6
• MYO7A
• NCOR1
• NLGN2
• NLGN3
• NOX3
• NPAS3
• NPC1
• NR4A2
• NR4A3
• NUP153
• OPRD1
• OTC
• OTOG
• PER1
• PITX3
• PKD2L2
• PNPLA6
• POU4F3
• PPARGC1A
• PPFIA3
• PPM1F
• PTCHD1
• PTPRK
• RAB5B
• RGS4
• RNF214
• RTL10
• RXYLT1
• SCN1A
• SHANK2 (see above)
• SHANK3
• SIRT1
• SLC12A6
• SLC1A2
• SLC26A10
• SLC5A7
• SLC6A3
• SLC9A6
• SNAI2
• SNCA
• SOBP
• SYNGAP1
• SYT4
• TBC1D8
• TBX10
• TECPR2
• TIP
• TMIE
• UBA6
• USH1C
• USH1G
• VIM
• VLDLR
• WDR41
• WHRN
• ZBTB20
• ZEB1
• ZPLD1

38.2. Monogenetic causes of hyperactivity and hypoactivity¶

Cabana-Domínguez et al found 6 mouse models in which manipulation of the following genes induced hyperactivity and hypoactivity:¹⁴⁵

• GPX6
• HTT
• LEPR
• PSAP
• SHANK3
• SLC6A8

38.3. Monogenetic causes of impulsivity¶

Cabana-Domínguez et al found 4 mouse models in which manipulation of the following genes induced impulsivity:¹⁴⁵

• CADM1
• COMT
• PER1
• SHANK3

38.4. Monogenetic causes of attention problems¶

Cabana-Domínguez et al found 5 mouse models in which manipulation of the following genes induced inattention:¹⁴⁵

• COMT
• PSEN1 (lack of attention maintenance)
• PTCHD1
• SNAP25
• TARDBP (executive dysfunction)