Case Report ARTICLE
Compound heterozygosity for novel truncating variants in the LMOD3 gene as the cause of polyhydramnios in two successive fetuses
- 1First Affiliated Hospital of Sun Yat-sen University, China
- 2Jiangmen Central Hospital, China
- 3INSERM UMR1078 Génétique, Génomique Fonctionnelle et Biotechnologies, France
- 4School of Medicine, Cardiff University, United Kingdom
Polyhydramnios is sometimes associated with genetic defects. However, establishing an accurate diagnosis and pinpointing the precise genetic cause of polyhydramnios in any given case represents a major challenge because it is known to occur in association with over 200 different conditions. Whole exome sequencing (WES) is now a routine part of the clinical workup, particularly with diseases characterized by atypical manifestations and significant genetic heterogeneity. Here we describe the identification, by means of WES, of novel compound heterozygous truncating variants in the LMOD3 gene [i.e., c.1412delA (p.Lys471Serfs*18) and c.1283dupC (p.Gly429Trpfs*35)] in a Chinese family with two successive fetuses affected with polyhydramnios, thereby potentiating the prenatal diagnosis of nemaline myopathy (NM) in the proband. LMOD3 encodes leiomodin-3, which is localized to the pointed ends of thin filaments and acts as a catalyst of actin nucleation in skeletal and cardiac muscle. This is the first study to describe the prenatal and postnatal manifestations of LMOD3-related NM in the Chinese population. Of all the currently reported NM-causing LMOD3 nonsense and frameshifting variants, c.1412delA generates the shortest truncation at the C-terminal end of the protein, underscoring the critical role of the WH2 domain in LMOD3 structure and function. Survey of the prenatal phenotypes of all four known LMOD3-related severe NM cases served to identify fetal oedema as a novel presenting feature that may provide an early clues for to facilitate prenatal diagnosis of the disease.
Keywords: LMOD3, Nemaline myopathy, Polyhydramnios, Prenatal Diagnosis, Truncating variants, whole exome sequencing
Received: 24 May 2019;
Accepted: 13 Aug 2019.
Copyright: © 2019 Wang, Zhu, Du, Li, Lin, Férec, Cooper, Chen and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mx. Yi Zhou, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong Province, China, firstname.lastname@example.org