Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

Abstract

Purpose: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. Methods:Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes.Results: Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. Conclusion:Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.

Characterizing the morbid genome of ciliopathies

“…The clinical features of the index (15DG2466) for one of these families with mutation in NEK4 are described in Additional file 3: supplemental clinical data. In three families, the affected members were found to share similar phenotypes, which have been recently published with the acronym DREAM-PL to highlight the main clinical features (dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly) [14, 15]. The fifth family displayed congenital hydrocephalus, synpolydactyly, and complex congenital heart disease, and no likely candidate was identified on exome sequencing.…”

Biallelic variants in CTU2 cause DREAM‐PL syndrome and impair thiolation of tRNA wobble U34

“…Representative clinical images of the unpublished patients are shown in Figure . Families 1, 2, 3, and 4 have the original founder variant NM_001012759.1:c.873G>A, r.738_873del, p. (Thr247Alafs*21) (ClinVar VCV000585016), and have been reported with full clinical details elsewhere (Shaheen et al, , ). The index in Family 5 is a 2 years old Omani child with DREAM‐PL phenotype lacking lissencephaly and polydactyly; Table ).…”

Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice

“…Two children aged 7 and 12 years from an extended consanguineous Arab family from Northern Saudi Arabia were previously identified [27]. On comparison with the Amish family, significant similarity in the clinical features was noted.…”

“…The variant was not listed in the Exome Variant Server (NHLBI GO Exome Sequencing Project (ESP), Seattle, WA; http://evs.gs.washington.edu/EVS/), 1000 Genomes browser (http://browser.1000genomes.org/index.html) or the Exome Aggregation Consortium (ExAC) database (http://exacbroadinstitute.org/). Interestingly, HYAL2 had recently been identified as a candidate gene as a cause of short stature and facial dysmorphism in a study of multiplex consanguineous families [27]. This study undertook genetic studies in 33 heterogeneous families with dysmorphic and other systemic clinical manifestations, and identified a sequence alteration in HYAL2 as a possible cause of the clinical features in a single family comprising two affected individuals (Fig 1A, Family 2).…”