Publications about genetic testing for neurological disorders
  1. Syndromic autism gene panel

Syndromic autism gene panel

June 15, 2018

Disease summary:

Autism spectrum disorders (ASD) are a clinically heterogeneous group of disorders that share common features of impaired social relationships, language and communication skills, as well as repetitive behaviors or a specific and very narrow range of interests. Symptoms develop gradually, and about 50-70% of children with autism are identified as intellectually disabled1 with lifelong disability requiring intensive parental, school, and social support 2, 3.

Autism can be associated with a syndromic phenotype, commonly characterized by dysmorphic features, microcephaly and seizures.

In 20-25% of cases with autism a genetic cause can be identified2-7. Chromosomal disorders (~5%), copy number variants (CNVs; chromosomal microdeletions and duplication syndromes) (10–20%), and single-gene disorders (~5%) 8. Pathogenic variants in many single genes have been associated with autism, including genes AP3B1, BLOC1S3, BLOC1S6, C10ORF11, DTNBP1, EDN3, EDNRB, GPR143, HPS1, HPS3, HPS4, HPS5, HPS6, KIT, LYST, MC1R, MITF, MLPH, MYO5A, OCA2, PAX3, RAB27A, SLC24A5, SLC45A2, SNAI2, SOX10, TYR, TYRP1 (Table 1) 9-19

X-linked, autosomal dominant, autosomal recessive

2-4/10,000 4 to 20/10,000 6

Major clinical symptoms 1, 2, 3:

  • Impaired social interaction
  • Impaired communication
  • Repetitive and stereotypic behaviors

Additional symptoms1, 2, 3:

  • Hyper- and hyposensitivity to sound and touch
  • Stereotypic behavior around food and their presentation
  • Abnormal sleep pattern (>60%)
  • Seizures (>25%)
  • Tantrums and/or self-injurious and aggressive behaviors
  • Impaired motor development with toe walking, hypotonia, general clumsiness
  • Catatonia syndrome (>15%)
  • Obesity
  • Presence of the specific behavioral changes and other autism-associated clinical feature
  • Positive family history of autism
  • Identification of a pathogenic variant in one of the associated genes (Table 1)

There is no cure for autism, however many symptomatic treatments can relieve symptoms1, 2, 3:

  • Psychosocial therapies, psychotherapy, cognitive behavioral psychotherapy, social skill interventions
  • Pharmacological treatments, including atypical antipsychotics, antidepressants, mood stabilizers
  • Supplements including vitamins, minerals, Omega-3 Fatty acids and others
  • Ongoing clinical trials investigating potential therapeutic effects of new drugs 
  • Developmental delay (global, language, intellectual or motor delay)
  • Intellectual disability
  • Attention deficit hyperactivity disorder
  • Mood disorders (anxiety disorder, obsessive compulsive disorder) or psychoses
  • Rett syndrome
  • Epileptic encephalopathy
  • Chromosomal abnormalities-associated syndromes (Angelman syndrome, trisomy 22)

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • Syndromic autism NGS Panel Plus which includes sequencing of the genes ADNP, ADSL, ALDH5A1, AMT, ANKRD11, ARID1B, BRAF, CACNA1C, CDKL5, CHD2, CHD7, CNTNAP2, CREBBP, DHCR7, EHMT1, FOXG1, FOXP1, GRIP1, HDAC8, HOXA1, HPRT1, MAGEL2, MECP2, MED12, MID1, NHS, NIPBL, NRXN1, NSD1, PCDH19, POGZ, PQBP1, PTEN, PTPN11, RAD21, RAI1, SCN1A, SCN2A, SETD2, SLC6A1, SLC6A8, SMC1A, SMC3, TBL1XR1, TCF4, TSC1, TSC2, UBE3A, VPS13B, ZEB2
  • Syndromic autism NGS Panel Plus + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data
  • Individuals with a positive family history of syndromic autism
  • Individuals with most common symptoms of syndromic autism (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of syndromic autism can allow for genetic counseling and may direct medical management.

Table 1. Overview of the genes in Syndromic autism panel:

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ADNP 611386 Helsmoortel-van der Aa syndrome AD 7
ADSL 608222 Adenylosuccinase deficiency AR 9
ALDH5A1 610045 Succinic semialdehyde dehydrogenase deficiency AR 2
AMT 238310 Glycine encephalopathy AR 9
ANKRD11 611192 KBG syndrome AD 21
ARID1B 614556 Coffin-Siris syndrome 1 AD 47
BRAF 164757 Cardiofaciocutaneous syndrome; Adenocarcinoma of lung, somatic; Noonan syndrome 7; LEOPARD syndrome 3 AD 18
CACNA1C 114205 Timothy syndrome; Brugada syndrome 3 AD 30
CDKL5 300203 Epileptic encephalopathy, early infantile, 2 XL D 18
CHD2 602119 Epileptic encephalopathy, childhood-onset AD 5
CHD7 608892 CHARGE syndrome; Hypogonadotropic hypogonadism 5 with or without anosmia AD 89
CNTNAP2 604569 Cortical dysplasia-focal epilepsy syndrome; Pitt-Hopkins like syndrome 1; Autism susceptibility 15 AR 29
CREBBP 600140 Rubinstein-Taybi syndrome 1 AD 28
DHCR7 602858 Smith-Lemli-Opitz syndrome AR 6
EHMT1 607001 Kleefstra syndrome 1 AD 13
FOXG1 164874 Rett syndrome, congenital variant AD 16
FOXP1 605515 Mental retardation with language impairment and with or without autistic features AD 9
GRIP1 604597 Fraser syndrome 3 AR 2
HDAC8 300269 Cornelia de Lange syndrome 5 XL D 6
HOXA1 142955 Athabaskan brainstem dysgenesis syndrome; Bosley-Salih-Alorainy syndrome 2
HPRT1 308000 Lesch-Nyhan syndrome; HPRT-related gout XL R 7
MAGEL2 605283 Schaaf-Yang syndrome AD 6
MECP2 300005 Mental retardation, X-linked, syndromic 13; Mental retardation, X-linked syndromic, Lubs type; Autism susceptibility, X-linked 3; Encephalopathy, neonatal severe; Rett syndrome; Rett syndrome, atypical; Rett syndrome, preserved speech variant Isolated cases, MF, XL, XL D, XL R 16
MED12 300188 Ohdo syndrome, X-linked; Opitz-Kaveggia syndrome; Lujan-Fryns syndrome XL R 18
MID1 300552 Opitz GBBB syndrome, type I XL R 7
NHS 300457 Cataract 40, X-linked; Nance-Horan syndrome XL, XL D 6
NIPBL 608667 Cornelia de Lange syndrome 1 AD 32
NRXN1 600565 Pitt-Hopkins-like syndrome 2; Schizophrenia, susceptibility to, 17 AR 40
NSD1 606681 Sotos syndrome 1; Leukemia, acute myeloid AD 27
PCDH19 300460 Epileptic encephalopathy, early infantile, 9 XL 11
POGZ 614787 White-Sutton syndrome AD 7
PQBP1 300463 Renpenning syndrome XL R 3
PTEN 601728 Bannayan-Riley-Ruvalcaba syndrome; Malignant melanoma, somatic; Cowden syndrome 1; Lhermitte-Duclos syndrome; Prostate cancer, somatic; Squamous cell carcinoma, head and neck, somatic; VATER association with macrocephaly and ventriculomegaly; Macrocephaly/autism syndrome; Meningioma; Endometrial carcinoma, somatic; Glioma susceptibility 2 AD, AR 22
PTPN11 176876 LEOPARD syndrome 1; Metachondromatosis; Noonan syndrome 1; Leukemia, juvenile myelomonocytic, somatic AD 11
RAD21 606462 Cornelia de Lange syndrome 4 AD 12
RAI1 607642 Smith-Magenis syndrome AD, Isolated cases 7
SCN1A 182389 Epilepsy, generalized, with febrile seizures plus, type 2; Febrile seizures, familial, 3A; Epileptic encephalopathy, early infantile, 6 (Dravet syndrome); Migraine, familial hemiplegic, 3 AD 131
SCN2A 182390 Seizures, benign familial infantile, 3; Epileptic encephalopathy, early infantile, 11 AD 54
SETD2 612778 Luscan-Lumish syndrome AD 10
SLC6A1 137165 Myoclonic-atonic epilepsy AD 2
SLC6A8 300036 Cerebral creatine deficiency syndrome 1 XL R 20
SMC1A 300040 Cornelia de Lange syndrome 2 XL D 9
SMC3 606062 Cornelia de Lange syndrome 3 AD 26
TBL1XR1 608628 Pierpont syndrome; Mental retardation, autosomal dominant 41 AD 2
TCF4 602272 Pitt-Hopkins syndrome; Corneal dystrophy, Fuchs endothelial, 3 AD 32
TSC1 605284 Tuberous sclerosis-1; Lymphangioleiomyomatosis; Focal cortical dysplasia, type II, somatic AD 71
TSC2 191092 Lymphangioleiomyomatosis, somatic; ?Focal cortical dysplasia, type II, somatic; Tuberous sclerosis-2 AD 148
UBE3A 601623 Angelman syndrome Isolated cases 19
VPS13B 607817 Cohen syndrome AR 20
ZEB2 605802 Mowat-Wilson syndrome AD 34