Identification of a novel PCNT founder pathogenic variant in the Israeli Druze population

Karin Weiss; Nina Ekhilevitch; Lior Cohen; Sharon Bratman-Morag; Rachel Bello; Ariel F Martinez; Yarin Hadid; Liran I Shlush; Alina Kurolap; Tamar Paperna; Adi Mory; Hagit N Baris; Maximilian Muenke

doi:10.1016/j.ejmg.2019.03.007

Identification of a novel PCNT founder pathogenic variant in the Israeli Druze population

Eur J Med Genet. 2020 Feb;63(2):103643. doi: 10.1016/j.ejmg.2019.03.007. Epub 2019 Mar 25.

Authors

Karin Weiss¹, Nina Ekhilevitch², Lior Cohen³, Sharon Bratman-Morag⁴, Rachel Bello⁵, Ariel F Martinez⁶, Yarin Hadid⁷, Liran I Shlush⁸, Alina Kurolap², Tamar Paperna⁹, Adi Mory⁹, Hagit N Baris¹⁰, Maximilian Muenke⁶

Affiliations

¹ Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA; The Genetics Institute, Rambam Health Care Campus, Haifa, 3109601, Israel.
² The Genetics Institute, Rambam Health Care Campus, Haifa, 3109601, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, 3525433, Israel.
³ Genetics Institute, Schneider Children's Medical Center, Petah Tikva, 49202, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
⁴ Internal Medicine B, Rambam Health Care Campus, Haifa, Israel.
⁵ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel; The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
⁶ Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
⁷ The Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, Haifa, Israel.
⁸ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
⁹ The Genetics Institute, Rambam Health Care Campus, Haifa, 3109601, Israel.
¹⁰ The Genetics Institute, Rambam Health Care Campus, Haifa, 3109601, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, 3525433, Israel. Electronic address: hb_feldman@rambam.health.gov.il.

PMID: 30922925
DOI: 10.1016/j.ejmg.2019.03.007

Abstract

Majewski Osteodysplastic Primordial Dwarfism type II (MOPDII) is a form of dwarfism associated with severe microcephaly, characteristic skeletal findings, distinct dysmorphic features and increased risk for cerebral infarctions. The condition is caused by bi-allelic loss-of-function variants in the gene PCNT. Here we describe the identification of a novel founder pathogenic variant c.3465-1G > A observed in carriers from multiple Druze villages in Northern Israel. RNA studies show that the variant results in activation of a cryptic splice site causing a coding frameshift. The study was triggered by the diagnosis of a single child with MOPDII and emphasizes the advantages of applying next generation sequencing technologies in community genetics and the importance of establishing population-specific sequencing databases.

Keywords: Druze; Founder; Microcephalic primordial dwarfism; PCNT.

Publication types

Case Reports

MeSH terms

Adolescent
Alleles
Antigens / genetics*
Cell Line, Tumor
DNA Mutational Analysis
Dwarfism / diagnosis
Dwarfism / genetics
Exome Sequencing
Facies
Female
Fetal Growth Retardation / diagnosis
Fetal Growth Retardation / genetics
Founder Effect*
Genetic Association Studies* / methods
Genetic Predisposition to Disease*
Genetic Testing
Humans
Israel
Male
Microcephaly / diagnosis
Microcephaly / genetics
Mutation*
Osteochondrodysplasias / diagnosis
Osteochondrodysplasias / genetics
Pedigree
Phenotype

Substances

Antigens
pericentrin

Supplementary concepts

Microcephalic Osteodysplastic Primordial Dwarfism, Type II