3. Monogenetic causes of ADHD

Monogenetic causes refers to genes in which certain gene variants can trigger disorders that are associated with ADHD symptoms.
As a monogenetic cause of ADHD, we have included genes in which at least 50% of people with ADHD develop ADHD in certain variants. The numbers in brackets indicate the prevalence of ADHD in certain gene variants of the named gene.

• 3. Monogenetic causes of ADHD
  • 3.1. CAPRIN1, Cell Cycle Associated Protein 1 (82 %)
  • 3.2. PHF21A, PHD Finger Protein 21A (78 %)
  • 3.3. TSC1, TSC Complex Subunit 1 (30 to 60 %)
  • 3.4. CHD8 (approx. 50 %)
  • 3.5. ODC1, ornithine decarboxylase 1 (Bachmann-Bupp syndrome, BABS)
  • 3.6. ANKRD11, Ankyrin Repeat Domain Containing 11
  • 3.7. ANKRD17, Ankyrin Repeat Domain Containing 17
  • 3.8. KMT2B, lysine methyltransferase 2B
  • 3.9. H1-4
  • 3.10. SRRM2, Serine/Arginine Repetitive Matrix 2

3. Monogenetic causes of ADHD¶

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

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.¹

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:²

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

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

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.³

PHF21A is associated with:⁴

• Intellectual developmental disorder with behavioral abnormalities
  • severe (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)
• Hypotension (70 %)
• ASS (50 %)
• Sleep disorders (33.33%)

Related metabolic pathways:

• Infectious diseases
• Chromatin organization

Paralog: PHF21B

3.3. 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

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 HERC1.⁵

Tsc1-mTORC1 signaling controls striatal dopamine release And cognitive flexibility.⁶

TSC1 is associated with

• tuberous sclerosis
• Lymphangioleiomyomatosis

Related signal paths:

• MTOR signaling
• Gene expression (transcription)

Tuberous sclerosis is associated with ADHD⁷⁸ in 30 to 60 % of people with ADHD and with neuropsychiatric manifestations such as ADHD, ASD or mental retardation in 90 %.⁹
The Austrian Tuberous Sclerosis Association offers the TAND checklist for tuberous sclerosis on.

3.4. CHD8 (approx. 50 %)¶

CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by¹⁰

• 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)

3.5. 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.¹¹
ODC1 is associated with:

• Sleeping sickness
• Bachmann-Bupp syndrome
  • Bachmann-Bupp syndrome (BABS) is characterized by¹²
    • 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) indicates 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

3.6. ANKRD11, Ankyrin Repeat Domain Containing 11¶

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

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.¹³
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.¹⁴
    KBG goes hand in hand with¹⁵
    • 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

3.7. 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

ANKRD17 is associated with:

• ANKRD17-related neurodevelopmental syndrome¹⁶
  • 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

3.8. 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.¹⁷
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.¹⁸
  • 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.¹⁸¹⁹

3.9. H1-4¶

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.²⁰

H1-4 is associated with

• Hist1h1e syndrome (Rahman syndrome)²¹
  • 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

3.10. SRRM2, Serine/Arginine Repetitive Matrix 2¶

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 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.²²

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:²³²⁴

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