A Maternal Loss‐of‐Function Variant in KHDC3L Gene Causes a Range of Adverse Pregnancy Outcomes: A Case Report

• Published in: Molecular genetics & genomic medicine 2025-01, Vol.13 (1), p.e70051-n/a
• Main Authors: Anvar, Zahra, Jafarpour, Farnoosh, Jahromi, Bahia Namavar, Riccio, Andrea, Nasr‐Esfahani, Mohammad Hossein, Cubellis, Maria Vittoria
• Format: Article
• Language: English
• Subjects: Abortion, Habitual - genetics; Adult; biparental hydatidiform mole; Clinical Report; DNA methylation; Embryos; Female; Gene sequencing; Genes; Genetic screening; Genetic testing; Genomes; Gestational age; Homozygote; Humans; Hydatidiform Mole - genetics; Hydatidiform Mole - pathology; Implantation; Infertility; Loss of Function Mutation; Miscarriage; Mutation; Neonates; Pregnancy; Premature birth; Proteins; recurrent pregnancy loss; RNA-Binding Proteins - genetics; Stem cells; subcortical maternal complex; Surrogate mothers; Ultrasonic imaging; Uterus; Whole genome sequencing; whole‐exome sequencing
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.70051

ABSTRACT Background The KHDC3L gene encodes a component of the subcortical maternal complex (SCMC). Biallelic mutations in this gene cause 5%–10% of biparental hydatidiform moles (BiHM), and a few maternal deletions in KHDC3L have been identified in women with recurrent pregnancy loss (RPL). Method In this study, we had a patient with a history of 10 pregnancy or neonatal losses, including spontaneous abortions, neonatal deaths, and molar pregnancy. Whole‐exome sequencing (WES) was performed for genetic diagnostic testing. Results We found a homozygous deleterious variant in the start codon of KHDC3L (c. 1A>G, p.M1V), which probably results in non‐translation or the production of a truncated protein. Conclusion This is the first report of a maternal loss‐of‐function variant in KHDC3L gene in a patient experiencing various types of pregnancy loss. This case report broadens the understanding of KHDC3L's pathogenic variants and phenotypic spectrum, consistent with its crucial role during human pre‐ and post‐implantation development. The model generated by Alphafold Protein Structure Database (Q587J8) for wild‐type KHDC3L protein product from residue 1 to 103. Beta strands are represented as arrows, with residues 1–14, which would be probably absent in the mutated protein, colored in red.