The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders

Abstract

This study investigated the phenotypic manifestations of interstitial duplications of chromosome 15 that involve the Prader-Willi/Angelman syndrome critical region (PWACR). Twenty-one affected individuals from six families were evaluated in detail, using standardized and semi-standardized measures of intelligence, psychopathology, and physical anomalies. Special attention was placed on determining the prevalence of autism spectrum disorders as well as the relationship between the parental origin of the duplication and the phenotypic effects. Assessments of the affected individuals were compared with evaluations of the unaffected relatives from the same families. Results indicated that duplications in the region were associated with variable degrees of intellectual impairments and motor coordination problems. Four of the subjects received a diagnosis of pervasive developmental disorder. Three of these cases were probands and only one met criteria for classic autism. There was very little evidence of the duplication cosegregating with autism spectrum disorder diagnosis. Paternally inherited duplications were significantly less likely to give rise to phenotypic effects. The findings indicate that duplications in the PWACR give rise to developmental delay but not necessarily autism spectrum disorders. They also suggest that phenotypic expression is dependent on the parental origin of the duplication and implicate maternally active genes in the pathogenesis of the developmental impairments. Further research will be required to clarify the range and basis of the phenotypic manifestations.

A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands

“…Chromosome 15q11-13 has been suggested to contain a susceptibility gene for autism based on several reports of chromosome abnormalities. 11 More distally, at 51.21 cM, we found association with marker D15S198 and for the two-marker segment D15S198-D15S643, and Shao et al 41 identified a region from 43.5 to 62.4 cM. On chromosome 6q marker D6S1652 (at 92.85 cM) appeared to be associated with autism and related PDDs.…”

“…4,5 Based on genome-wide scans, screening of possible candidate genes, and studies of association between autism and chromosome abnormalities, candidate regions of autism have been suggested on chromosome 2q, [6][7][8] 7q, 9,10 and 15q. 11,12 However, no susceptibility genes have yet been identified, and except for a few specific etiological factors like the fragile X syndrome, tuberous sclerosis, and maternally inherited duplication of 15q11-13, the etiology of autism is largely unknown. 13 The use of isolated populations is a powerful approach in the search for disease genes and has facilitated the identification of candidate chromosome regions involved in monogenic diseases 14 and in some complex diseases, for example, uric acid nephrolithiasis.…”

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.…”

Segmental haplosufficiency: transmitted deletions of 2p12 include a pancreatic regeneration gene cluster and have no apparent phenotypic consequences

“…26 Re-examination of the parents in the case of Browne et al 24 suggests that paternal duplications of 15q11.2-q13 can have phenotypic consequences, but much milder than those associated with maternal duplications of the same segment. 27 The lack of a 'second hit' is likely to explain the lack of retinoblastoma in the mother of a child with the 13q14 deletion. 28 Nevertheless, over half the 56 carriers in this category were phenotypically unaffected.…”