Matching Two Independent Cohorts ValidatesDPH1as a Gene Responsible for Autosomal Recessive Intellectual Disability with Short Stature, Craniofacial, and Ectodermal Anomalies

Abstract

Recently, Alazami and colleagues 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 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. Sharing of data via web-based anonymous data exchange servers will play an increasingly important role towards more efficient identification of the molecular basis for rare Mendelian disorders.

Meta-Analysis of Genome-Wide Association Studies Identifies Three Loci Associated With Stiffness Index of the Calcaneus

“…Aside from BMD, many of our candidate genes are associated with other phenotypes as well. For example, DPH1 (17p13.3) is a susceptibility gene for short stature and craniofacial anomalies . TSR1 (17p13.3) and POLQ (3q13.33) have been reported to be candidates for influencing aortic root size and multiple myeloma, respectively.…”

“…For example, DPH1 (17p13.3) is a susceptibility gene for short stature and craniofacial anomalies. (45) TSR1 (17p13.3) and POLQ (3q13.33) have been reported to be candidates for influencing aortic root size (46) and multiple myeloma, (47) respectively. Importantly, FTNB and RAB15, were identified as novel heel bone property-related genes in our study.…”

Elsahy–Waters syndrome is caused by biallelic mutations in CDH11

“…We have attempted to address this challenge by publishing large scale tentative disease‐gene links to facilitate post‐publication matchmaking (Alazamiet al, ; Shaheen, Patel, et al, ; Shaheen, Szymanska, et al, ; Shamseldin et al, , ). This paper is one of many that resulted from a successful and quick post‐publication matchmaking (Breuss et al, ; Elo et al, ; Gai et al, ; Loucks et al, ; Muggenthaler et al, ; Palmer et al, ; Picker‐Minh et al, ; Wheway et al, ). In 2017, we briefly described the index in Family 1 as one of 35 patients each harboring a candidate mutation in 33 genes with no established link to human diseases (Anazi et al, ).…”

Genetic Causes of Craniosynostosis: An Update

“…In 4 individuals from a North American genetic isolate and 4 individuals of a nonrelated consanguineous Saudi Arabian family, homozygous mutations were identified in DPH1 [Alazami et al, 2015;Loucks et al, 2015]. The patients had developmental delay, central nervous system malformations (including Dandy-Walker malformations, cerebellar vermis hypoplasia, and posterior fossa cysts), dysmorphic features (including scaphocephaly, prominent forehead, hypertelorism, downslanting palpebral fissures, epicanthal folds, low-set ears, depressed nasal bridge, micrognathia, and sparse scalp hair), ventricular septal defect, short stature, and early lethality [Alazami et al, 2015;Loucks et al, 2015].…”

“…The patients had developmental delay, central nervous system malformations (including Dandy-Walker malformations, cerebellar vermis hypoplasia, and posterior fossa cysts), dysmorphic features (including scaphocephaly, prominent forehead, hypertelorism, downslanting palpebral fissures, epicanthal folds, low-set ears, depressed nasal bridge, micrognathia, and sparse scalp hair), ventricular septal defect, short stature, and early lethality [Alazami et al, 2015;Loucks et al, 2015]. DPH1 is involved in the biosynthesis of diphthamide [Liu et al, 2004].…”