Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay

• Published in: Human genetics Vol. 130; no. 4; pp. 517 - 528
• Main Authors: Burnside, Rachel D., Pasion, Romela, Mikhail, Fady M., Carroll, Andrew J., Robin, Nathaniel H., Youngs, Erin L., Gadi, Inder K., Keitges, Elizabeth, Jaswaney, Vikram L., Papenhausen, Peter R., Potluri, Venkateswara R., Risheg, Hiba, Rush, Brooke, Smith, Janice L., Schwartz, Stuart, Tepperberg, James H., Butler, Merlin G.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.10.2011; Springer; Springer Nature B.V
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adolescent; Adult; Angelman Syndrome - genetics; Autism; Autistic Disorder - genetics; Behavior; Biological and medical sciences; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; Chromosome Deletion; Chromosome Disorders; Chromosomes; Chromosomes, Human, Pair 15 - genetics; Classical genetics, quantitative genetics, hybrids; Comparative Genomic Hybridization; Developmental Disabilities - genetics; Disease Susceptibility; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Female; Fundamental and applied biological sciences. Psychology; Gene Duplication; Gene Expression Profiling; Gene Function; Genes; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Genotype & phenotype; Human; Human Genetics; Humans; In Situ Hybridization, Fluorescence; Infant; Infant, Newborn; Language Development Disorders - genetics; Male; Medical sciences; Mental Disorders - genetics; Metabolic Diseases; Middle Aged; Molecular Medicine; Nervous system; Nervous system (semeiology, syndromes); Neurology; Oligonucleotide Array Sequence Analysis; Original Investigation; Speech Disorders - genetics; Young Adult; United States > US; Copy Number Change; Copy Number Alteration; Angelman Syndrome; Intellectual Disability; Secondary Alteration; Chromosomal aberration; Proximal; Communication disorder; Language retardation; Dysfunction; Deletion; Genetics; Nervous system; Developmental disorder; Language disorder
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-011-0970-4

The proximal long arm of chromosome 15 has segmental duplications located at breakpoints BP1–BP5 that mediate the generation of NAHR-related microdeletions and microduplications. The classical Prader-Willi/Angelman syndrome deletion is flanked by either of the proximal BP1 or BP2 breakpoints and the distal BP3 breakpoint. The larger Type I deletions are flanked by BP1 and BP3 in both Prader-Willi and Angelman syndrome subjects. Those with this deletion are reported to have a more severe phenotype than individuals with either Type II deletions (BP2–BP3) or uniparental disomy 15. The BP1–BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes that are not imprinted. Reports of mutations or disturbed expression of these genes appear to impact behavioral and neurological function in affected individuals. Recently, reports of deletions and duplications flanked by BP1 and BP2 suggest an association with speech and motor delays, behavioral problems, seizures, and autism. We present a large cohort of subjects with copy number alteration of BP1 to BP2 with common phenotypic features. These include autism, developmental delay, motor and language delays, and behavioral problems, which were present in both cytogenetic groups. Parental studies demonstrated phenotypically normal carriers in several instances, and mildly affected carriers in others, complicating phenotypic association and/or causality. Possible explanations for these results include reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances.