Matching Two Independent Cohorts Validates DPH1 as a Gene Responsible for Autosomal Recessive Intellectual Disability with Short Stature, Craniofacial, and Ectodermal Anomalies

• Published in: Human mutation Vol. 36; no. 10; pp. 1015 - 1019
• Main Authors: Loucks, Catrina M., Parboosingh, Jillian S., Shaheen, Ranad, Bernier, Francois P., McLeod, D. Ross, Seidahmed, Mohammed Z., Puffenberger, Erik G., Ober, Carole, Hegele, Robert A., Boycott, Kym M., Alkuraya, Fowzan S., Innes, A. Micheil
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.10.2015; John Wiley & Sons, Inc
• Subjects: Adolescent; Bone and Bones - abnormalities; Child, Preschool; Cohort Studies; Craniosynostoses - genetics; DPH1; Dwarfism - genetics; Ectodermal Dysplasia - genetics; Female; Genetic disorders; Genomics; Genotype & phenotype; Humans; Information Dissemination; Intellectual disabilities; intellectual disability; Intellectual Disability - genetics; Male; Matchmaker Exchange; Minor Histocompatibility Antigens; Mutation; Mutation, Missense; Pedigree; rare disorders; Sensenbrenner; Tumor Suppressor Proteins - genetics; Young Adult; Sensenbrenner; Matchmaker Exchange; DPH1; rare disorders; intellectual disability
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.22843

ABSTRACT Recently, Alazami et al. (2015) identified 33 putative candidate disease genes for neurogenetic disorders. One such gene was DPH1, in which a homozygous missense mutation was associated with a 3C syndrome‐like phenotype in four patients from a single extended family. Here, we report a second homozygous missense variant in DPH1, seen in four members of a founder population, and associated with a phenotype initially reminiscent of Sensenbrenner syndrome. This postpublication “match” validates DPH1 as a gene underlying syndromic intellectual disability with short stature and craniofacial and ectodermal anomalies, reminiscent of, but distinct from, 3C and Sensenbrenner syndromes. This validation took several years after the independent discoveries due to the absence of effective methods for sharing both candidate phenotype and genotype data between investigators. Sharing of data via Web‐based anonymous data exchange servers will play an increasingly important role toward more efficient identification of the molecular basis for rare Mendelian disorders. DPH1 was recently proposed as a candidate gene for syndromic intellectual disability after a homozygous mutation was associated with a 3C syndrome‐like phenotype in four patients from a single extended family. Here we report a second homozygous missense variant in DPH1, seen in four members of a founder population, and associated with a phenotype initially reminiscent of Sensenbrenner syndrome. This post‐publication ‘match’ validates DPH1 as a gene underlying syndromic intellectual disability with short stature and craniofacial and ectodermal anomalies, reminiscent of, but distinct from, 3C and Sensenbrenner syndromes. This validation took several years after the independent discoveries due to the absence of effective methods for sharing both candidate phenotype and genotype data between investigators, and underscores the value of novel mechanisms for matchmaking going forward.