Table 1.
Main genetic disorders associated with autistic syndrome.
| Genetic Disorder [References] | Estimated Rate (%) of the Disorder in Autism | Estimated Rate (%) of Autism in the Disorder | Degree of Intellectual Disability (ID) | Possible Autistic Behaviors | Other Possible Behaviors | Other Possible Symptoms |
|---|---|---|---|---|---|---|
| Chromosomal Disorders | ||||||
| Maternal * 15q11–q13 duplication [26,27,28,29,30,31,32,33,34,35,36,37,38] | 1–2 | 80–100 | Severe | Severe autistic syndrome with severe expressive language impairment | Hyperactivity and aggression | Seizures (75%), hypotonia, genitor/urinary abnormalities |
| Angelman syndrome * (maternal 15q11-q13 deletion, paternal uniparental disomy, mutations of UBE3A that encodes an ubiquitin E3 ligase) [35,39,40,41,42,43,44,45,46,47,48] | 1 | 48–80 | Severe | No language, stereotypies, sameness | Attention Deficit with Hyperactivity Disorder (ADHD), paroxysmal laughter, tantrums | Facial dysmorphism, microcephaly, seizures (>1 year), ataxia and walking disturbance |
| Prader–Willi syndrome * (maternal uniparental disomy at 15q11-q13, paternal deletions) [35,49,50,51,52,53,54,55,56,57,58] Paternal 15q11-q13 duplication (only few cases reported to be associated with autism): behavioral phenotype similar to Prader–Willi syndrome [58,59,60] |
Not Available (NA) | 19–37 | Mild to moderate | Motor and verbal stereotypies, rituals | Hyperphagia, obsessive-compulsive traits, temper tantrums | Obesity, growth delay and hypogonadism, facial dysmorphism, Hypotonia |
| Phelan–McDermid * syndrome (Inherited, de novo deletions at 22q13.3 leading to loss of SHANK 3) 22q13.3 duplication [20,61,62,63,64,65,66,67,68,69,70] | NA | 75–84 | Severe | Variable autistic syndrome with social communication impairments, including delayed or absent verbal language | Global developmental delay, atatonia in adolescence and adulthood | Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures |
| 16p11.2 duplication 16p11.2 deletion [71,72,73,74,75,76,77] | 1 | 33 | Severe | Severe autistic syndrome with speech impairment | Gross and fine coordination problems, SCH (Schizophrenia), anxiety, ADHD | Hypotonia (Multiple congenital anomalies are possible with more distal region) |
| Inverted duplication/deletion 8p21–23 [78,79] | NA | 30–57 | Variable | Mild to moderate autistic syndrome with absent or delayed verbal language | ADHD | Minor facial dysmorphism, hypotonia, agenesis of the corpus callosum, possible heart defect |
| Genetic disorder [References] | Estimated rate (%) of the disorder in autism | Estimated rate (%) of autism in the disorder | Degree of intellectual disability (ID) | Autistic behaviors | Other behaviors | Other symptoms |
| Down syndrome * (trisomy 21) [80,81,82,83,84] | 2 | 5–10 | Variable but usually severe when autism | Severe autistic syndrome | - | Facial dysmorphism, heart and intestine malformations |
| Smith–Magenis syndrome (17p11.2 deletion) [85,86,87,88] | <1 | 80–100 | Variable | Self-injurious and stereotyped behaviors, sameness | Tantrums, possible social contact, sleep disturbance | Facial dysmorphism, peripheral neuropathy, hypotonia |
| Potocki–Lupski syndrome (17p11.2 duplication) [89] | NA | 50–100 | Normal to moderate | Decreased eye contact, motor manierisms or posturing, sensory hypersensitivity or preoccupation, repetitive behaviors or interests, lack of appropriate functional or symbolic play and lack of joint attention | Developmental delay, language impairment, and cognitive impairment | hypotonia, poor feeding and failure to thrive in infancy, oral-pharyngeal dysphagia, obstructive and central sleep apnea, structural cardiovascular abnormalities, electroencephalography (EEG), abnormalities, and hypermetropia |
| 2q37 deletion [90,91,92,93,94] | <1 | 25–35 | Mild to moderate | Severe communication impairment, stereotypies | Hypotonia, hyperactivity, Obsessive-Compulsive Disorder (OCD), aggression, sleep disturbance | Facial dysmorphism, microcephaly, growth delay/short stature, intestine and heart malformations, seizure |
| 22q11.21 duplication and 22q11 deletion (DiGeorge/Vélocardio-facial syndrome) [95,96,97,98,99,100] | NA | <10 | Normal to severe ID | Autistic syndrome, Pervasive Developmental Disorder-Not Otherwise Specified PDD-NOS (ICD-10 criteria) | Learning disability, anxiety, ADHD, oppositional-defiant disorder, OCD, motor impairment | Facial dysmorphism, microcephaly, growth delay/short stature, craniofacial abnormalities/cleft palate, heart defect, hypotonia |
| 1q21.1 Copy-Number Variation (CNV) (1q21.1 deletion/duplication) [101,102,103,104] | NA | <30 | Normal to mild ID | Autistic syndrome, PDD-NOS (ICD-10 criteria) | Developmental delay, learning disability, anxiety, ADHD, aggression, SCZ and hallucination | Microcephaly (deletion) Macrocephaly (duplication) |
| Williams-Beuren syndrome * (7q11.23 deletion) and Reciprocal 7q11.23 duplication syndrome [105,106,107,108,109,110,111,112,113,114,115,116,117] | <1 | <10 | Mild to moderate | Autistic syndrome | Overfriendliness, over talkativeness, visual spatial deficit, hyperacusis, feeding and sleep problems | Facial dysmorphism, short stature, heart and endocrine malformations, hypercalcemia |
| Turner syndrome * (most common monosomy For X chromosome) [37,118,119] | NA | 3 | Usually normal IQ | Females monosomic for the maternal chromosome X score significantly worse on social adjustment and verbal skills | - | Short stature, skeletal abnormalities, absence of ovarian function, webbed neck, lymphedema in hands and feet, heart defects and kidney problems |
| Beckwith–Wiedemann * syndrome (abnormal expression of imprinted genes on chromosome 11p15.5 such as IGF2 and/or CDKN1C) [120,121,122,123] | NA | 6.8 (replication needed) | Usually normal IQ | Autistic syndrome | - | Pre- and postnatal overgrowth (hemihyperplasia, macroglossia, visceromegaly) and increased risk of embryonal tumors |
| Isodicentric chromosome 15 or duplication/inversion 15q11 [124,125] | NA | NA | Moderate to severe | Autistic behavior | Developmental delay and intellectual deficit, epilepsy | Early central hypotonia |
| Ito hypomelanosis [126,127] | NA | NA | Inconstant | Asperger syndrome(high functioning autism) or atypical autism | Psychomotor delay and cognitive deficit | hypopigmented skin lesions along the Blaschko lines, motor delay, seizures, microcephaly or macrocephaly, hypotonia, ophthalmological abnormalities |
| Single Gene Disorders | ||||||
| CHARGE syndrome * (CHD7, 8q21.1) [128,129,130,131,132,133] | <1 | 15–50 | Variable but often normal IQ | Variable autistic syndrome | Hyperactivity, obsessive-compulsive traits, tic disorders | Coloboma of the eye, Heart defects, Atresia of the nasal choane, Retardation of growth and/or development, Genital/urinary abnormalities, Ear abnormalities/deafness |
| Tuberous sclerosis (TSC1, 9q34) (TSC2, 16p13.3) [134,135,136] | 1–4 | 25–60 | Variable | Severe autistic syndrome | Learning disorder | Ectodermal anomalies, renal lesions, seizures |
| PTEN macrocephaly syndromes (PTEN, 10q23.31) [137,138,139,140,141,142] | 4 in ASD with macro-cephaly | NA | Severe | Autistic syndrome and language delay | = | Progressive macrocephaly, developmental delay, macrosomy, tumors in adulthood |
| Rett’s syndrome * (MECP2, Xq28) [117,143,144,145,146,147,148,149] | <1 in female | 61–100 | Severe | Stereotyped hand movements, absence of language, loss of social engagement | Stagnation stage (6–18 months) in girls, then regression stage (12–36 months), pseudostationary t stage (2–10 years), l and late motor t deterioration (>10 years) | Head growth deceleration, progressive motor neuron (gait and truncal apraxia, ataxia, decreasing mobility) and respiratory (hyperventilation, breath holding, apnea) symptoms |
| San Filippo syndrome # (SGSH, 17q25.3) [150,151,152,153] | 1 replication needed | 80–100 | Severe | Language impairment, autistic withdrawal, stereotyped behaviors impulsivity, inappropriate affects | Progressive loss of acquisitions | Motor regression, hepatomegaly |
| Cerebral folate deficiency # (FOLR1, 11q13.4) [154,155,156,157] | NA | NA | Variable | Autistic syndrome including especially social interaction and language impairment | irritability, movement (such as tremors) and gait disturbances with ataxia, sleep problems | Psychomotor regression, epilepsy, developmental delay, deceleration of head growth, dystonia/hypotonia, visual and hearing deficit |
| Smith–Lemli–Opitz syndrome # (DHCR7, 1q12–13) [158,159,160,161,162,163] | NA | 50 | Variable | Self-injurious behaviors, stereotypies (“opisthokinesis”) language impairment | Sensory hyper-reactivity, irritability, sleep disturbance | Facial dysmorphism, cleft palate, congenital heart disease, hypospadias, 2–3 toe syndactyly |
| Phenylketonuria # (PAH, 12q22-q24.1) [20,164,165] | NA | NA | Severe | Self-injurious behavior, lack of social responsiveness | Temper tantrums, hyperactivity | Eczema, hypertonia, seizures, hypo-pigmentation |
| Adenylosuccinate lyase deficiency # (ASL, 22q13.1–13.2) [166,167,168,169,170] | <1 | 80–100 | Variable | Severe autistic syndrome | - | Seizures |
| Creatine deficiency syndrome # (GAMT, 19p13.3) (CRTR, Xq28) [171,172,173,174] | <1 | 80–100 | Severe | Severe autistic syndrome with poor language | - | Seizures, hypotonia |
| SHANK 3 (22q13.3) [175,176,177] | <1 | NA | NA | Severe autistic syndrome with no language | - | - |
| Neurexin family: Neurexin 1 (NRX1, 2p16.3) [178,179,180,181,182] | 1 | NA | Variable | Autistic syndrome | Hyperactivity, depression, learning disability, but also normal behavior | Seizures, hypotonia, facial dysmorphism? |
| Contactin Associated Protein-like 2 (CNTNAP2, 7q35) [183,184,185] | NA | NA | Variable | Autistic syndrome including verbal language impairment | - | Seizures |
| Contactin 4 (CNTN4, 3p26.2–3p26.3) [186,187,188,189] | <1 | NA | Variable | Autistic syndrome, PDD-NOS (ICD-10 criteria) | Visual spatial impairment, regression | Facial dysmorphism, developmental delay, hypotonia, ptosis. |
| Cell adhesion molecule-1 (CADM1, 11q22.3–23.2) [190,191,192] | NA | NA | NA | Autistic syndrome with especially social communication impairment including verbal language deficit | - | - |
| Protocadherin 10 (PCDH10, 4q28) [193] | <1 | NA | NA | Autistic syndrome | - | - |
| Neuroligin family: Neuroligin 3 (NLG3, Xq13) Neuroligin 4 (NLG4, Xq22.33) [194,195,196] | <1 | NA | Variable | Severe autistic syndrome, PDD-NOS (ICD-10 criteria) | Regression | Tic |
| Fragile X * (FMR1, Xq27.3) [191,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222] | 0–8 | 0–33 | Variable | Poor eye contact , social anxiety, language deficit and stereotypies | Hyperactivity with attention deficit, sensory hyper-reactivity | Facial dysmorphism, macro-orchidism |
| Neurofibromatosis type 1 [109,223,224,225] | NA | 21–40 | inconstant | Restrictive/repetitive behaviors and severe social-communicative impairments | Cognitive deficits and learning difficulties | Café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, multiple neurofibromas |
| Sotos syndrome [226,227] | NA | 70 (replication needed) | Mild to severe | Self-injurious behavior, physical aggression, and destruction | - | Facial dysmorphism, overgrowth of the body in early life with macrocephaly |
| Aarskog syndrome [228,229] | NA | NA | - | Variable autistic syndrome | Learning and behavioral disabilities | facial, limbs and genital features, acromelic short stature |
| Cornelia de Lange syndrome [117,230,231] | NA | 43 (replication needed) | Variable | Self-injury, excessive repetitive behaviors and expressive language deficits | Psychomotor delay, language acquisition difficulties | Facial dysmorphism, severe growth delay, abnormal hands and feet, and constant brachymetacarpia of the first metacarpus, various other malformations (heart, kidney, etc.) |
| Joubert syndrome [232] | NA | <40 | severe intellectual deficit to normal intelligence | Autistic syndrome | - | Facial dysmorphism, abnormal respiratory pattern, nystagmus, hypotonia, ataxia, and delay in achieving motor milestones |
| Cohen syndrome [117,233,234,235] | NA | 54 (replication needed) | variable | Atypical autism | Often sociable with a cheerful disposition, learning and behavioral problems | Microcephaly, facial dysmorphism, hypotonia, myopia, retinal dystrophy, neutropenia and truncal obesity |
| Lujan–Fryns syndrome [236] | NA | NA | Mild to moderate | Autistic-like disorder | Behavioral problems, emotional instability, hyperactivity and shyness, schizophrenia | Tall, marfanoid stature, facial dysmorphism, hypernasal voice and generalized hypotonia |
| Noonan syndrome [237,238,239] | NA | 15 (replication needed) | Mild | ASD | Poor feeding in infancy | Short stature, facial dysmorphism and congenital heart defects |
| Moebius syndrome [128,240,241] | NA | 0–45 | Inconstant, mild | ASD | Delayed walk development | Oculofacial paralysis, strabismus |
| Helsmoortel–Van der Aa syndrome (ADNP-related ID/ASD) [242] | 0.17 | 100 | Mild to severe | ASD, behavioral problems, sleep disturbance | Delayed developmental milestones (walking between 19 months and 4.5 years, and speech ranging from sentences to no words) | Facial dysmorphism, hypotonia, seizures, feeding difficulties, visual problems (hypermetropia, strabismus, cortical visual impairment), and cardiac defects |
| Timothy syndrome (CACNA1C) [243] | NA | 50–70 (replication needed) | Inconstant, mild to severe | ASD | Language, motor, and generalized cognitive impairment | Facial dysmorphism, rate-corrected QT (QTc) interval >480 ms, unilateral or bilateral cutaneous syndactyly, heart defects, seizures |
Adapted from Tordjman et al. [25]. # These genetic disorders are metabolic disorders (the list is not exhaustive). * The asterisk indicates the existence of epigenetic mechanisms observed in these genetic disorders (the list is not exhaustive).