10 research outputs found
Characterizing the morbid genome of ciliopathies
Background Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete. Results We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their âmutation loadâ beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population. Conclusions Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies
Additional file 2: Table S3. of Characterizing the morbid genome of ciliopathies
Clinical and genomic data for all cases in the study. (XLSX 83 kb
Additional file 5: Table S4. of Characterizing the morbid genome of ciliopathies
Identification of TXNDC15 interacting proteins using tandem affinity purification (TAP). The list of 224 unique proteins is significantly enriched in known or predicted ciliary proteins. (XLSX 30 kb
Additional file 8: Table S1. of Characterizing the morbid genome of ciliopathies
List of diagnostic criteria used to clinically classify each ciliopathy. (XLSX 10 kb
Additional file 3: of Characterizing the morbid genome of ciliopathies
Supplemental clinical data: clinical details for the affected cases with mutations in novel candidate genes. (DOCX 35 kb
Additional file 1: Figure S1. of Characterizing the morbid genome of ciliopathies
Bar graph showing the percentage of the main features for each distinct ciliopathy syndrome. (PPTX 70 kb
Additional file 7: Table S6. of Characterizing the morbid genome of ciliopathies
List of common variants with MAF of >0.01 that are listed as âÂÂdisease-causingâ variants in HGMD for known ciliopathy genes. (XLSX 12 kb
Additional file 6: Table S5. of Characterizing the morbid genome of ciliopathies
Ciliopathy disease burden in the population for each pathogenic variant identified in known ciliopathy genes. (XLSX 19 kb
Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.
Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
Keywords: KMT2A; MLL1; Wiedemann-Steiner syndrome; hypertrichosis; syndromic intellectual disability; syndromic short stature.Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania
United States Department of Health & Human Services
National Institutes of Health (NIH) - USA
NIH National Center for Advancing Translational Sciences (NCATS)
United States Department of Health & Human Services
National Institutes of Health (NIH) - USA
Hartwell Foundatio