Prenatal ultrasonic presentation in fetuses with monogenic neurologic and neuromuscular diseases: a retrospective study

This is the authors' abstract. We don't add key points for this paper.

Abstract Background: The prenatal phenotype of neurological and neuromuscular monogenic diseases remains unclear. This study aimed to identify and explore prenatal ultrasonic presentation in fetuses with monogenic neurologic and neuromuscular diseases and to increase our knowledge on causal variants and novel candidate genes associated with fetal phenotypes. Methods: This retrospective study included 30 fetuses genetically diagnosed with or suspected of having neurologic and neuromuscular monogenic diseases who underwent prenatal trio-exome sequencing between January 2018 and May 2023. We systematically reviewed data on prenatal ultrasonic presentation, genetic characteristics, and genotype-phenotype relationships in a cohort of 30 fetuses. Some cases in this cohort study have been previously published as separate studies. Results: The disease spectrum of the 30 families included 27 diseases, including central nervous system diseases, neuromuscular diseases, congenital myopathy, mitochondrial diseases, and neurological genetic syndromes. The ultrasound abnormalities of the fetuses included abnormal fetal gestures and movements(18/30), polyhydramnios (15/30), increased nuchal translucency or nuchal fold (11/30), dysmorphic facial features (8/30), and brain malformations (6/30). Of the 40 variants detected, 35 were classified as pathogenic or likely pathogenic and 5 were of undetermined significance according to the American College of Medical Genetics and Genomics guidelines. The inheritance patterns were autosomal dominant (17/30; 57%), autosomal recessive (10/30; 33%), and X-linked recessive (3/30; 10%). Thirteen (13/30; 43%) fetuses achieved a definite genetic diagnosis, including known or novel variants of the recognized disease genes. Sixteen (16/30, 54%) fetuses were highly or probably suspected to be associated with genetic variants, and one fetus was found to have gene variants that did not explain the phenotype. Conclusions: The main clinical manifestations of prenatal ultrasonic presentation of neurological and neuromuscular monogenic diseases are abnormal fetal gestures, movements, and amniotic fluid volume, which might provide important clues for prenatal diagnosis. Trio-exome sequencing comprehensively detected and delineated various genomic variants that are causative. Our study expands our understanding of the prenatal phenotypic spectrum of monogenic neurological and neuromuscular diseases.