Table1 clinical features and genetic findings of the prenatal cases with skeletal dysplasia

1

26 yrs, gravid 1 para 0

25 weeks

A narrow thorax and short limbs (humeri lengths 2.0 cm and femurs lengths 2.2 cm, < -3.18 SD) with pleural and peritoneal effusion and bilateral pyelectasis; no polydactyly and other remarkable malformations

Terminated at 28 weeks

DYNC2H1 NM_001080463.2

c.3133C > T;p.Gln1045Ter

The variant causes a C-terminally truncated protein at codon 1045. The full-length DYNC2H1 protein consists of 4307 amino acid residues, and thus the variant is considered loss-of-function. (PVS1)

The variant is absent in population databases including ExAC, 1000G, and gnomAD. (PM2)

Likely Pathogenic

c.6809G > A;p.Arg2270Gln

The variant is absent in population databases including ExAC, 1000G, and gnomAD. (PM2)

The online tool Mutation Taster predicts that the arginine is conserved across species and glutamine substitution is disease causing. (PP3)

Uncertain significance

2

29 yrs, gravid 1 para 0

38 weeks + 5 days

Short long bones of the limbs (humeri lengths 5.6 cm and femurs lengths 6.1 cm, < -3.13 SD), high echo spot in gallbladder crystals, and high density of umbilical coiling. Amniotic fluid index was 22.1 cm

Naturally delivered at term when the diagnostic ES was still undergoing

IFT172 NM_015662.3

c.1513C > T;p.Arg505Trp

The variant possesses a frequency of 0.0003 and 0.0009, respectively, in ExAC and gnomAD.(PM2)

Uncertain significance

c.4540-5 T > A

The variant has not been reported in ExAC, 1000G and gnomAD. (PM2)

The CADD online tool analysis suggests that the -5 position is a splice acceptor site, mutation of which probably affects RNA splicing. (PP3)

Uncertain significance

3

24 yrs, gravid 1 para 0

22 weeks + 6 days

Shortened ribs (bell-shaped), narrow thorax, shortened long bones of the limbs (humeri lengths 2.8 cm and femurs lengths 3.2 cm, < -3.04 SD), enlarged kidneys, and enhanced renal parenchymal echo

Terminated at 25 getation weeks before the molecular diagnosis was completed

WDR19 NM_025132.4

c.2363 + 1G > A

The variant destroys the canonical splice donor site in intron 20 and theoretically results in absent or disrupted protein product. (PVS1)

The variant has a frequency of 4.76e-05 in gnomAD. (PM2)

Likely pathogenic

c.2596G > C;p.Gly866Arg

The variant has not been reported in the ExAC, 1000G and gnomAD databases. (PM2)

In silico analysis (Mutation Taster) predicts that the substitution is deleterious to the protein. (PP3)

Uncertain significance

4

28 yrs

28 weeks after ovulation induction

Intrauterine growth restriction (IUGR), abdominal circumference < 3^rd percentile and femurs lengths < -3.77 SD

Loss of follow-up

DYNC2H1 NM_001080463.2

c.1390C > T;p.Arg464Ter

The variant produces an early truncated protein with a loss of the majority of amino acid residues, and thus the variant is considered non-functional. (PVS1)

The variant has been reported in gnomAD with a frequency of 5.59e-05, but not in ExAC or 1000G. (PM2)

Likely pathogenic

c.337C > T;p.Arg113Trp

The variant is listed in ExAC and gnomAD with a frequency of 1.66e-05 and 4.80e-05,respectively.(PM2)

The variant has previously been reported to be in trans position with the pathogenic variant c.3353del (p.Ser1118IlefsTer46) to cause ATD (PM3)

Uncertain significance