title: Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome).
abstract: BACKGROUND
  The clinical features of Phelan-McDermid syndrome (also known as 22q13 deletion syndrome) are highly variable and include hypotonia, speech and other developmental delays, autistic traits and mildly dysmorphic features. Patient deletion sizes are also highly variable, prompting this genotype-phenotype association study.
  
  
  METHODS
  Terminal deletion breakpoints were identified for 71 individuals in a patient cohort using a custom-designed high-resolution oligonucleotide array comparative genomic hybridisation platform with a resolution of 100 bp.
  
  
  RESULTS
  Patient deletion sizes were highly variable, ranging from 0.22 to 9.22 Mb, and no common breakpoint was observed. SHANK3, the major candidate gene for the neurologic features of the syndrome, was deleted in all cases. Sixteen features (neonatal hypotonia, neonatal hyporeflexia, neonatal feeding problems, speech/language delay, delayed age at crawling, delayed age at walking, severity of developmental delay, male genital anomalies, dysplastic toenails, large or fleshy hands, macrocephaly, tall stature, facial asymmetry, full brow, atypical reflexes and dolichocephaly) were found to be significantly associated with larger deletion sizes, suggesting the role of additional genes or regulatory regions proximal to SHANK3. Individuals with autism spectrum disorders (ASDs) were found to have smaller deletion sizes (median deletion size of 3.39 Mb) than those without ASDs (median deletion size 6.03 Mb, p=0.0144). This may reflect the difficulty in diagnosing ASDs in individuals with severe developmental delay.
  
  
  CONCLUSIONS
  This genotype-phenotype analysis explains some of the phenotypic variability in the syndrome and identifies new genomic regions with a high likelihood for causing important developmental phenotypes such as speech delay.
authors: Office of Bioinformatics and Epidemiology, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA. smsaras@g.clemson.edu
authors: Sara M
authors: SM
authors: Sarasua
authors: Alka
authors: A
authors: Dwivedi
authors: Luigi
authors: L
authors: Boccuto
authors: Jonathan D
authors: JD
authors: Rollins
authors: Chin-Fu
authors: CF
authors: Chen
authors: R Curtis
authors: RC
authors: Rogers
authors: Katy
authors: K
authors: Phelan
authors: Barbara R
authors: BR
authors: DuPont
authors: Julianne S
authors: JS
authors: Collins
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007805:Language Development Disorders / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D009419:Nerve Tissue Proteins; D010641:Phenotype; D012720:Severity of Illness Index
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human