Cytogenetic and molecular analysis of inv dup(15) chromosomes observed in two patients with autistic disorder and mental retardation

Abstract

A variety of distinct phenotypes has been associated with supernumerary inv dup(15) chromosomes. Although different cytogenetic rearrangements have been associated with distinguishable clinical syndromes, precise genotype‐phenotype correlations have not been determined. However, the availability of chromosome 15 DNA markers provides a means to characterize inv dup(15) chromosomes in detail to facilitate the determination of specific genotype‐phenotype associations. We describe 2 patients with an autistic disorder, mental retardation, developmental delay, seizures, and supernumerary inv dup(15) chromosomes. Conventional and molecular cytogenetic studies confirmed the chromosomal origin of the supernumerary chromosomes and showed that the duplicated region extended to at least band 15q13. An analysis of chromosome 15 microsatellite CA polymorphisms suggested a maternal origin of the inv dup(15) chromosomes and biparental inheritance of the two intact chromosome 15 homologs. The results of this study add to the existing literature which suggests that the clinical phenotype of patients with a supernumerary inv dup(15) chromosome is determined not only by the extent of the duplicated region, but by the dosage of genes located within band 15q13 and the origin of the normal chromosomes 15. © 1996 Wiley‐Liss, Inc.

Genetics and Child Psychiatry: II Empirical Research Findings

“…Also, the chromosomal findings have provided too many leads for them to be of much value. The one possible exception concerns the association between autism and a partial tetrasomy of chromosome 15 (Baker, Piven, Schwartz, & Patil, 1994 ;Flejter et al, 1996 ;Gillberg et al, 1991 ;Hotopf & Bolton, 1995). It is not yet known whether this association has any meaning, but it may have.…”

Unusual features in children with inv dup(15) supernumerary marker: a study of genotype-phenotype correlation in Taiwan

“…The small one seemed to be noncontributory to the patient's phenotype, other factors may play a role in the developmental delay. The eect exerted upon the phenotype is determined not only by the extent of the duplicated region, but the dosage of genes located within band 15q11-13 and the origin of the normal chromosome [8]. Most ESACs in this study were of maternal origin.…”

Characterization of an Autism-Associated Segmental Maternal Heterodisomy of the Chromosome 15q11–13 Region

“…Number of case reports described an association of de novo, maternally derived proximal 15q chromosome abnormalities with autism (Cook et al, 1997(Cook et al, , 1998Flejter et al, 1996;Schroer et al, 1998;WeidmerMikhail, Sheldon, & Ghaziuddin, 1998;Wolpert, Pericak-Vance, Abramson, Wright, & Cuccaro, 2000a;Wolpert et al, 2000b). Of these 15q chromosome abnormalities, idic(15) chromosome of maternal origin is most frequently associated with autism (Crolla et al, 1995;Huang et al, 1997).…”

“…The small dicentric chromosomes without the PWS/AS region are often familial or de novo and not associated with any clinical abnormality (Cheng, Spinner, Zackai, & Knoll, 1994). Large supernumerary idic(15) chromosomes containing the PWACR are usually maternal in origin and have a wide range of developmental problems that can include severe mental retardation, seizure disorders, various degrees of developmental delay, and some autism phenotype (Bolton et al, 2001;Cook et al, 1997;Eggermann et al, 2002;Flejter et al, 1996;Gillberg et al, 1991;Roberts et al, 2002b;Robinson et al, 1993b;Schinzel et al, 1994). Paternal inheritance also has been reported in some cases (Eggermann et al, 2002;Werner et al, 2004) Individuals with supernumerary isodicentric(15) chromosomes often have three copies of maternal genes from the chromosome 15q11-q13 region have adverse developmental outcomes and also meet criteria for autism (Cheng et al, 1994;Gillberg et al, 1991;Leana-Cox et al, 1994).…”

“…Although it might be easier to draw a correlation between the degree of PWACR gene dosage and the severity of developmental outcomes in these individuals (Borgatti et al, 2001;Flejter et al, 1996;Mignon et al, 1996;Robinson et al, 1993b), it is more difficult to find a correlation between gene dosage and autism phenotype. The severity of autistic symptoms varied widely in individuals with idic(15).…”