Nada Derar1, Zuhair N Al-Hassnan2,3, Mohammed Al-Owain2,3, Dorota Monies1,4, Mohamed Abouelhoda1,4, Brian F Meyer2,4, Nabil Moghrabi1, Fowzan S Alkuraya5,6,7. 1. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 2. Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 3. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 4. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. 5. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa. 6. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa. 7. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
Abstract
PURPOSE: Wolf-Hirschhorn syndrome (WHS) is a genomic disorder with a recognizable dysmorphology profile caused by hemizygosity at 4p16.3. Previous attempts have failed to map the minimal critical locus to a single gene, leaving open the possibility that the core phenotypic components of the syndrome are caused by the combined haploinsufficiency of multiple genes. METHODS: Clinical exome sequencing and "reverse" phenotyping. RESULTS: We identified two patients with de novo truncating variants in WHSC1, which maps to the WHS critical locus. The phenotype of these two individuals is consistent with WHS, which suggests that haploinsufficiency of WHSC1 is sufficient to recapitulate the core phenotype (characteristic facies, and growth and developmental delay) of this classic microdeletion syndrome. CONCLUSION: Our study expands the list of microdeletion syndromes that are solved at the single-gene level, and establishes WHSC1 as a disease gene in humans. Given the severe nature of the reported variants, the full phenotypic expression of WHSC1 may be further expanded by future reports of milder variants.
PURPOSE: Wolf-Hirschhorn syndrome (WHS) is a genomic disorder with a recognizable dysmorphology profile caused by hemizygosity at 4p16.3. Previous attempts have failed to map the minimal critical locus to a single gene, leaving open the possibility that the core phenotypic components of the syndrome are caused by the combined haploinsufficiency of multiple genes. METHODS: Clinical exome sequencing and "reverse" phenotyping. RESULTS: We identified two patients with de novo truncating variants in WHSC1, which maps to the WHS critical locus. The phenotype of these two individuals is consistent with WHS, which suggests that haploinsufficiency of WHSC1 is sufficient to recapitulate the core phenotype (characteristic facies, and growth and developmental delay) of this classic microdeletion syndrome. CONCLUSION: Our study expands the list of microdeletion syndromes that are solved at the single-gene level, and establishes WHSC1 as a disease gene in humans. Given the severe nature of the reported variants, the full phenotypic expression of WHSC1 may be further expanded by future reports of milder variants.
Entities:
Keywords:
De novo; Exome; Intellectual disability; Methyltransferase
Authors: David R Murdock; Hongzheng Dai; Lindsay C Burrage; Jill A Rosenfeld; Shamika Ketkar; Michaela F Müller; Vicente A Yépez; Julien Gagneur; Pengfei Liu; Shan Chen; Mahim Jain; Gladys Zapata; Carlos A Bacino; Hsiao-Tuan Chao; Paolo Moretti; William J Craigen; Neil A Hanchard; Brendan Lee Journal: J Clin Invest Date: 2021-01-04 Impact factor: 14.808
Authors: Elizabeth S Barrie; Maria P Alfaro; Ruthann B Pfau; Melanie J Goff; Kim L McBride; Kandamurugu Manickam; Erik J Zmuda Journal: Cold Spring Harb Mol Case Stud Date: 2019-08-01