Table 1 Summary of prenatal findings, suspected diagnosis, exome-sequencing results, and final diagnosis

From: Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management

Case	Gest	Ultrasound findings	Prenatal diagnosis	Fetal sequencing result	Inheritance	Classification	Outcome	Molecular diagnosis	Days to diagnosis ^a
1	25	Short leg bones; mild bowed femora	? Skeletal dysplasia	COL1A1 c.1168G>A p.(Ala390Thr) (het) NM_000088.3	Paternally inherited VUS	3^b HGMD: CM090256	LB	None made; mild femoral shortening and bowing on postnatal radiographs
2	13.5	Progressive short limbs, small chest, short ribs	SRPS	WDR34 c.882G>C p.(Lys294Asn) (hom)NM_052844.3	AR Biparental inheritance	4^b Novel^c	ToP at 16 weeks; no PM	Short-rib thoracic dysplasia 11	30
3	12	NT 7 mm, flexion deformities of wrists with single forearm bones and bent humeri, short femurs, pleural effusions	? Skeletal dysplasia	RBM8A c.-21G>A (het) 484Kb deletion on 1q21.1 including RBM8A NM_005105.4	AR	5^b ClinVar: RCV000081257.4; RCV000023418.9	LB; bilateral radial aplasia, aplastic humerus, fixed flexed wrists and right knee; severe thrombocytopenia	Thrombocytopenia absent radius syndrome	27
4	13.4	Micromelia, short ribs, unossification vertebral bodies	Lethal skeletal dysplasia ? achondrogenesis	COL2A1 c.1969G>C p.(Gly657Arg) (het) NM_001844.4	De novo	4^b Novel^d	NND at 29 weeks; no PM	Type 2 collagenopathy	41
5	30	Late onset rhizomelic long bone shortening	? Achondroplasia but targeted FGFR3 analysis negative	FGFR3 c.833A>G p.(Tyr278Cys) (het) NM_000142.4	De novo	4^b ClinVar: RCV000017768.27; RCV000415056.1 HGMD: CM066083	LB; rhizomelia all limbs, prominent forehead	Hypochondroplasia	30
6	21	Generalized short long bones	? Skeletal dysplasia	GDF5 c.902G>A p.(Arg301Gln) (het) NM_001319138.1	Maternally inherited VUS	3^b Novel	LB	No diagnosis made; early delivery for placental insufficiency
7	14	Short long bones with acute angulation of femur, humerus, and radius.	? OI, ?Hypophospatasia	ALPL c.331G>A p.(Ala111Thr) (het) NM_000478.5	AD maternally inherited	4^b HGMD: CM980059	LB—X rays and compatible with hypophospatasia, increased urinary phosphoethanolamine	Hypophosphatasia	16
8	20	Mild shortening and bowing of leg bones	? OI	COL1A2 c.2835+1G>A (het) NM_000089.3	AD maternally inherited	5^b ClinVar: RCV000490660.1; RCV000490726.1 HGMD: CS042159	LB	Compatible with OI type IV	13
9	20	Mild shortening and bowing of femurs	? OI	IFITM5 c.119C>T p.(Ser40Leu) (het) NM_001025295.2	De novo	5^b ClinVar: RCV000351373.1; RCV000162330.3 HGMD: CM144605	ToP; PM compatible with OI	Compatible with OI (published data would classify as type V, but case published not typical of this category)	18
10	24	Short bowed femora. Other long bones ~3rd percentile	? Skeletal dysplasia	COL1A1 c.2362G>A p.(Gly788Ser) (het) NM_000088.3	De novo	5^b HGMD: CM070687	LB; X-rays and clinically compatible with moderate–severe OI	Compatible with OI type III/IV	19
11	21	Short, thick bowed femora, evidence of fractures; humerus short, abnormal shape	? Skeletal dysplasia	P3H1 (LEPRE1) c.2041C>T p.(Arg681*) (hom) NM_001243246.1	AR Bi-parental inheritance	5^b HGMD: CM086851	Ongoing	Compatible with OI type VIII	12
12	20	Long bones <3rd centile, small chest but ribs not short; no evidence of fractures	Skeletal dysplasia ? 3-M syndrome	OBSL1 c.1273dup p.(Thr425Asnfs*40) (hom)	AR Bi-parental inheritance	5^e HGMD: CI093475	Ongoing	3-M syndrome	12
13	22.4	Short long bones, epiphyseal stippling, contractures, irregular ossification of ribs	? Chondrodysplasia punctata	EBP c.451C>T p.(Gln151*) (het) NM_006579.2	De novo	5^e HGMD: CM023368	ToP; PM findings compatible with chondrodysplasia punctata	X-linked dominant chondrodysplasia punctata-2	11
14	26	All long bones and chest <5th percentile; bowed femora, talipes	? OI	COL1A1:c.2024_2028+1del (het) NM_000088.3	De novo	5^e Novel	Ongoing	Compatible with OI	13
15	23	All long bones <5th centile, abnormal head shape, short ribs	?Skeletal dysplasia	RECQL4 het c.1136G>A p.(Trp379*) NM_004260.3	AR maternal	4^e Novel	IUD; awaiting PM	None confirmed; single mutation in recessive gene—suggestive of Baller–Gerold syndrome	17
16		Short bowed and curved long bones, narrow chest, FL:AC ratio 0.06	?OI	COL1A1 c.3132_3140del p.(Ala1053_Gly1055del) (het) NM_000088.3	De Novo	5^e ClinVar: RCV000413092.1^f HGMD: CD013144	ToP subsequent to later ultrasound finding of a diaphragmatic hernia; PM awaited	Compatible with OI	15

AD, autosomal dominant; AR, autosomal recessive; FL:AC, femur length:abdominal circumference; Gest, gestation; HGMD, Human Gene Mutation Database; Het, heterozygote; Hom, homozygote; IUD, intrauterine death; LB, live birth; NND, neonatal death; NT, nuchal translucency; OI, osteogenesis imperfecta; PM, postmortem; SRPS, short-rib polydactyly syndrome; ToP, termination of pregnancy; VUS, variant of uncertain significance.
^aDays to diagnosis defined as time from receipt of sample in laboratory or normal array result to identification of variant.
^bClassified using the UK best practice guidelines prior to the United Kingdom’s adoption of American College of Medical Genetics and Genomics guidelines.¹⁴
^cThis variants affects a highly conserved amino acid and the majority of in silico analysis tools support the pathogenicity of this variant. The variant was shown to be homozygous in two affected fetuses in this family and heterozygous in both parents. The phenotype in both affected pregnancies was compatible with short-rib thoracic dysplasia 11. This variant has also been detected homozygously in a fetus with a similar phenotype in a poster published online by another laboratory.²⁹
^dThis variant affects a glycine residue within the Gly-X-Y repeat motif within the triple helical domain of the COL2A1 gene, which is a common mutational mechanism in collagenopathies.
^eClassified using the American College of Medical Genetics and Genomics guidelines.⁶
^fSame protein nomenclature—different nucleotide change.

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Table 1 Summary of prenatal findings, suspected diagnosis, exome-sequencing results, and final diagnosis

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