15q Duplication associated with autism in a multiplex family with a familial cryptic translocation t(14;15)(q11.2;q13.3) detected using array-CGH

• Published in: Clinical genetics Vol. 69; no. 2; pp. 124 - 134
• Main Authors: Koochek, M, Harvard, C, Hildebrand, MJ, Van Allen, M, Wingert, H, Mickelson, E, Holden, JJA, Rajcan-Separovic, E, Lewis, MES
• Format: Journal Article
• Language: English
• Published: Oxford, UK; Malden, USA Munksgaard International Publishers 01.02.2006; Blackwell
• Subjects: 14q; 15q; Adolescent; Adult; autism spectrum disorder (ASD); Autistic Disorder - genetics; Biological and medical sciences; Child; Child clinical studies; chromosome 6q; Chromosome Banding; Chromosomes, Human, Pair 14 - genetics; Chromosomes, Human, Pair 15 - genetics; Classical genetics, quantitative genetics, hybrids; comparative genomic hybridization (CGH); cryptic translocation; Developmental disorders; Family Health; Female; fluorescent in situ hybridization (FISH); Fundamental and applied biological sciences. Psychology; Gene Duplication; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genomics; Human; Humans; In Situ Hybridization, Fluorescence; Infant; Infant, Newborn; Infantile autism; intellectual disability; Male; Medical genetics; Medical sciences; microarray; microdeletion; microduplication; Molecular and cellular biology; Nucleic Acid Hybridization; Pedigree; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Translocation, Genetic - genetics; Chromosomal aberration; Microdeletion; fluorescent in situ hybridization (FISH); In situ; Fluorescence; Chromosome D14; Developmental disorder; Microarray; Cryptic; Spectrum; microduplication; Fluorescence in situ hybridization; Genetics; autism spectrum disorder (ASD); Neurological disorder; Chromosome translocation; Genetic mapping; Human; Nervous system diseases; Family study; Chromosome C6; Autism; Comparative genomic hybridization; cryptic translocation; Abnormal chromosome; comparative genomic hybridization (CGH); chromosome 6q, 14q, 15q; Chromosome duplication; intellectual disability
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2005.00560.x

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic aetiology. In approximately 1% of cases, duplication of the 15q11‐13 region has been reported. We report the clinical, array‐comparative genomic hybridization (CGH) and cytogenetic evaluation of two individuals from a multiplex family demonstrating autism due to a maternally inherited gain of 15q11‐13. Our findings indicate that unlike most 15q11‐13 gains, which are caused by interstitial duplication of this region or supernumerary marker chromosomes deriving from proximal 15q, the 15q gain in this family is the result of abnormal segregation of a cryptic familial translocation with breakpoints at 14q11.2 and 15q13.3. The affected members of this family were found to have a normal karyotype at >550 band resolution. This translocation was identified using the 1‐Mb resolution whole genome array (Spectral Genomics). The affected individuals have a gain of seven clones from proximal 15q, a loss of two clones from proximal 14q and a gain of two clones from 6q. Fluorescent in situ hybridization (FISH) analysis with clones from chromosomes 14 and 15, combined with DAPI reverse banding, showed an abnormal karyotype with one normal chromosome 15 and the der(15) t(14;15)(q11.2.;q13.3), resulting in the gain of proximal 15q and the loss of proximal 14q in affected individuals. The duplication of two clones from 6q in the affected subjects was also found in unaffected members of the family. Our findings suggest that the gain of 15q in autism may in some cases be due to cryptic translocations with breakpoints in the pericentromic regions of chromosome 15 and a different acrocentric chromosome. Variation in the size of pericentromic regions of any acrocentric chromosome may justify karyotype and FISH studies of autistic probands and their parents using probes from the 15q proximal region to determine recurrence risk for autism in some families.