Whole Exome Sequencing Aids The Diagnosis of Fetal Skeletal Dysplasia

Abstract

Background: Skeletal dysplasia is a complex group of bone and cartilage disorders with strong clinical and genetical heterogeneousity. Several types have prenatal phenotypes. And it is difficult to make a molecular diagnosis rapidly due to lacking family history and non-specific and limited clinical symptoms in utero. This study aims to diagnose 16 Chinese fetuses with skeletal dysplasia.Methods: Single nucleotide polymorphism-array (SNP-array) was performed in 12 of 16 samples. If no microdeletions or microreplications related to skeletal dysplasia were detected, whole-exome sequencing (WES) was adopted. And the last four cases only got whole-exome sequencing for analyzing copy number variants and single nucleotide variations at the same time.Results: Among the 16 cases, 12 patients received definitive diagnosis and we detected one deletion in DMD gene by SNP-array and 15 variants of 6 genes including FGFR3, COL1A1, COL1A2, ALPL, HSPG2 and DYNC2H1. 8 variants of COL1A1, COL1A2, ALPL and HSPG2 are novel. And somatic mosaicism in asymptomatic parent with mutations in COL1A1 or COL1A2 was observed.Conclusions: In general, our study expanded the prenatal phenotypes in Duchenne muscular dystrophy (DMD)/ Becker muscular dystrophy (BMD), found 8 novel variants and elucidated that the utilization of whole-exome sequencing improved the diagnosis yield of skeletal dysplasia and provided useful genetic counseling guidance for parents.

Application of whole exome sequencing in fetal cases with skeletal abnormalities

“…Both disorders have common clinical manifestations that involved in skeletal abnormalities ( Martinez et al., 2018 ; Stum et al., 2006 ), including bowing of the long bones. The phenotype was also presented in our cases and previous studies ( Tang et al., 2021 ).…”

“…All of these fetuses presented short long bones. c.1138G>A in the FGFR3 gene is a hotspot mutation ( Tang et al., 2021 ). A similar result also was described in COL1A1 c.2461G>A p (Gly821Ser) ( Ho Duy et al., 2016 ).…”

Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta‐analysis

“… 32 , 41‐48 , 33‐40 Eight studies targeted ES analysis more tightly using phenotype‐specific gene panels, 7 , 12 , 15 , 49‐53 while the remainder took a whole ES approach 8 ,. 13 , 62‐71 , 54 , 72‐81 , 55 , 82‐88 , 56‐61 Where stated (15 studies), 7 , 8 , 74 , 75 , 78 , 82 , 84 , 15 , 29 , 36 , 52 , 53 , 55 , 62 , 73 the median turnaround time for ES was 20 days (range 4–141). Studies included fetuses with a range of structural abnormality phenotypes, with some studies recruiting cases with fetal anomalies in a specific body system (e.g.…”

“…14,32,[41][42][43][44][45][46][47][48][33][34][35][36][37][38][39][40] Eight studies targeted ES analysis more tightly using phenotypespecific gene panels, 7,12,15,[49][50][51][52][53] while the remainder took a whole ES approach. 8,13,[62][63][64][65][66][67][68][69][70][71]54,[72][73][74][75][76][77][78][79][80][81]55,[82][83]…”

Whole Exome Sequencing Aids the Diagnosis of Fetal Skeletal Dysplasia

“…The manuscript was submitted as a preprint at Research Square (Tang et al, 2020 ). We thank all the healthy individuals and the family members for their participation and support in this study.…”