Identification of a Founder GLDN Variant Associated With "Lethal" Arthrogryposis in Nunavik Inuit: Implications for Obstetrical and Long-Term Survivors' Management.

Autor: McAdam A; Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada., Ito YA; Division of Genome Diagnostics, BC Children's and BC Women's Hospital, Vancouver, British Columbia, Canada., Richard M; Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Quebec, Canada.; Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada., Spiegelman D; Centre Hospitalier Universitaire mère-Enfant Sainte-Justine, Université de Montréal, Montréal, Quebec, Canada., Rochefort D; Montreal Neurological Institute-Hospital, McGill University Health Centre, Montreal, Quebec, Canada., Xiong L; Montreal Neurological Institute-Hospital, McGill University Health Centre, Montreal, Quebec, Canada., Oskoui M; Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.; Department of Pediatrics and Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada., Zielinski D; Division of Pediatric Respirology, Department of Pediatrics, McGill University Health Centre, Montreal, Quebec, Canada., Rouleau GA; Montreal Neurological Institute-Hospital, McGill University Health Centre, Montreal, Quebec, Canada., Zhou S; Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada.; Montreal Neurological Institute-Hospital, McGill University Health Centre, Montreal, Quebec, Canada., Boykott KM; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.; Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada., De Bie I; Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Quebec, Canada.; Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Dec 23, pp. e63974. Date of Electronic Publication: 2024 Dec 23.
DOI: 10.1002/ajmg.a.63974
Abstrakt: Biallelic variants in GLDN have recently been associated with lethal congenital contracture syndrome 11 (LCCS11), a form of fetal akinesia deformation sequence (FADS) with high neonatal mortality. In this report, we describe five individuals from two Canadian Inuit families originating from different communities in Nunavik all affected with FADS and harboring a rare homozygous missense variant, [NM_181789.4:c.82G >C p.(Ala28Pro)] in GLDN. Two pregnancies presented with significant obstetrical complications including placental abruption and hemorrhage. Four infants died shortly after birth, while one survived past the neonatal period. This individual, while apparently asymptomatic during infancy, then presented with progressive neuromuscular and respiratory compromise that became more evident in adolescence. Data from a Nunavik Inuit cohort demonstrated a minor allele frequency (MAF) of 0.03571 for this variant compared to 0.00001341 in the general population, suggesting a founder effect in the Nunavik Inuit population. Our findings support the presence of a founder variant associated with LCCS11 in Nunavik Inuit populations. Our data corroborate those of other reports, demonstrating that LCCS11 is not universally lethal, but long-term survivors are at risk of progressive neuromuscular compromise. We also highlight in this report the significant obstetrical complications associated with this fetal-onset condition.
(© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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