Autism and maternally derived aberrations of chromosome 15q

Abstract

Of the chronic mental disabilities of childhood, autism is causally least well understood. The former view that autism was rooted in exposure to humorless and perfectionistic parenting has given way to the notion that genetic influences are dominant underlying factors. Still, identification of specific heritable factors has been slow with causes identified in only a few cases in unselected series. A broad search for genetic and environmental influences that cause or predispose to autism is the major thrust of the South Carolina Autism Project. Among the first 100 cases enrolled in the project, abnormalities of chromosome 15 have emerged as the single most common cause. The four abnormalities identified include deletions and duplications of proximal 15q. Other chromosome aberrations seen in single cases include a balanced 13;16 translocation, a pericentric inversion 12, a deletion of 20p, and a ring 7. Candidate genes involved in the 15q region affected by duplication and deletion include the ubiquitin-protein ligase (UBE3A) gene responsible for Angelman syndrome and genes for three GABA(A) receptor subunits. In all cases, the deletions or duplications occurred on the chromosome inherited from the mother.

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

“…39 Several studies suggest that SHANK3 has a critical role also in other neurodevelopmental disorders such as schizophrenia and intellectual disability. 10,[40][41][42] In the present study, we screened two cohorts of ASD patients for SHANK3 mutations: 133 patients from SCAP 33 and 88 from Italy. We found five potentially pathogenic alterations (Table 1), resulting in a mutation rate of 2.3%, which is twice as high as the frequency of deleterious SHANK3 mutations reported in previous studies.…”

“…The SC group is composed of AD patients between the ages of 5 and 21 years from the South Carolina Autism Project (SCAP). 33 The diagnoses were established by the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS), and/or the Childhood Autism Rating Scale (CARS) tests. This cohort contained 122 isolated and 11 familial cases (at least one affected sibling), with 101 male and 32 female patients (ratio 3.1:1).…”

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…Regarding additional behavioural problems, a severe hyperactivity is often noticed. [19][20][21][22][23][24][25][26] Deletions of the maternal or paternal chromosome 15q11-13 regions are associated with two cytogenetic imprinting disorders, Angelman syndrome and Prader-Willi syndrome (PWS). Genomic imprinting describes the phenomenon of differences in gene expression between the allele inherited from the mother and the allele inherited from the father.…”

Angelman syndrome: a review of clinical and genetic aspects

“…8 This group is, however, likely to be heterogeneous and to include patients with other disorders. [51][52][53][54][55][56][57][58] Some of the diagnoses which must be excluded in this group are Rett syndrome, 59 60 the α thalassaemiamental retardation syndrome, 61 and the condition described by Mowat et al, which is now known to be the result of large scale deletions or point mutations within the ZFHX1B gene on chromosome 2. 62 63 The diagnosis of AS may also be considered in children with broader symptom complexes, such as cerebral palsy, Lennox-Gastaut syndrome, or mitochondrial disorders.…”

“…8 41 72-76 It has been shown, for example, that patients with chromosome 15 deletions are in general the most severely affected. They have a higher incidence of seizures, microcephaly, and hypopigmentation, 52 Repetto et al, 53 Schroer et al 55 greater delay in motor milestones, and absent speech. The more severe features are thought to be the result of haploinsufficiency for a number of genes within the 15q11-13 region.…”