Table 2 Summary of likely pathogenic/ pathogenic variants identified by WES in fetuses with structural anomalies

Fetus-parental trios

3084

Short long bone

Musculoskeletal system

FGFR3

NM_000142.4:

c.1138G > A

p.(G380R)

AD

hom (affected parents)

P

Achondroplasia

MIM:100,800

3033

Short nasal bone, single umbilical artery, nasal skin thickening, abnormal morphology of bilateral auricles

Craniofacial abnormalities

EP300

NM_001429.4:

c.5527dup▲

p.(Q1843Pfs*40)

AD

de novo het

P

Menke-Hennekam syndrome 2 MIM:618,333; Rubinstein Taybi syndrome 2

MIM:613,684

2964

Skeletal

dysplasia, short long bones

Musculoskeletal system

LBR

NM_002296.4:

c.1757G > A

p.(R586H)

c.1748G > A

p.(R583Q)

AR

compound het

LP

P

Greenberg skeletal dysplasia MIM:215,140

2949

Cystic hygroma, lymphocysts, hydrops fetalis, pleural effusion, flexion contracture, clubfoot

Multiple system

MYH3

NM_002470.4:

c.3247_3248 + 1del▲

AD

de novo het

LP

Arthrogryposis, distal, type 2 A MIM:193,700

5540

Lateral ventricle dilatation, ventricular abnormality, cardiac rhabdomyoma

Multiple system

TSC2

NM_000548.5:

c.5239_5256del▲

p.(I1747_Q1752del)

AD

de novo het

P

Tuberous sclerosis-2

MIM:613,254

2997

Renal dysplasia, cranial abnormalities

Genitourinary system

BBS2

NM_031885.4:

c.700 C > T

p.(R234*)

AR

hom

P

Bardet-Biedl syndrome 2 MIM:615,981

8222

Short long bone

Musculoskeletal system

EBP

NM_006579.3:

c.278 A > T

p.(D93V)

XLD

de novo het

LP

Chondrodysplasia punctata, X-linked dominant

MIM:302,960

2090

Hypoplasia of the lower limbs

Musculoskeletal system

MMP9

NM_004994.3:

c.151 C > T▲

p.(R51C)

c.929del▲

p.(G310Afs*28)

AR

compound het

LP

LP

Metaphyseal anadysplasia 2

MIM:613,073

2079

Short limb deformity, short long bone, bowed femur, polyhydramnios

Musculoskeletal system

FGFR3

NM_000142.4:

c.1138G > A

p.(G380R)

AD

de novo het

P

Achondroplasia

MIM:100,800

6431

Widen cerebellar medullary pool, left renal cyst, bipedal polydactyly

Multiple system

CPLANE1

NM_023073.3:

c.2854_2855insCT▲

p.(N952Tfs*13)

c.3599 C > T

p.(A1200V)

AR

compound het

LP

LP

Joubert syndrome 17

MIM:614,615

Orofaciodigital syndrome VI

MIM:277,170

8232

Widen cerebellar medullary pool, abnormal renal morphology, oligohydramnios

Multiple system

INVS

NM_014425.5:

c.796 + 5G > A

c.805_806del▲

p.(Q269Dfs*10)

AR

compound het

P

P

Nephronophthisis 2, infantile

MIM:602,088

2051

Short long bone, abnormality of the thorax

Musculoskeletal system

COL1A1

NM_000088.3:

c.2110G > A

p.(G704S)

AD

de novo het

P

Osteogenesis imperfecta

MIM:166,210

2014

Arthrogryposis

Musculoskeletal system

SMPD4

NM_017951.4:

c.387-1G > A

wes[hg38]chr2(13

0142742-130202459)x1 59.72 kb deletion

AR

compound het

P

LP

Neurodevelopmental disorder with microcephaly,

arthrogryposis, and structural brain anomalies

MIM:618,622

6411

Short femur length

Musculoskeletal system

FGFR3

NM_000142.4:

c.1620 C > A

p.(N540K)

AD

de novo het

P

Achondroplaia MIM:100,800

6429

Femoral

fracture

Musculoskeletal system

COL1A1

NM_000088.3:

c.3977T > G▲

p.(F1326C)

AD

de novo het

LP

Osteogenesis imperfecta

MIM:166,210

8233

Hypoplastic auricles, Webster’s cavity, polyhydramnios

Multiple system

EYA1

NM_000503.6:

c.1698 + 2T > C▲

AD

het (affected father)

LP

Otofaciocervical

syndrome MIM:166,780

5549

Short long bone

Musculoskeletal system

TTC21B

NM_024753.5:

c.3130_3131dup▲

p.(H1045Dfs*20)

c.2569G > A

p.(A857T)

AR

compound het

LP

LP

Short-rib thoracic dysplasia 4 with or without polydactyly MIM:613,819

5509

Developmental malformation

Multiple system

MKS1

NM_017777.4:

c.1407 + 66G > A▲

c.1411dup

p.(E471Gfs*178)

AR

compound het

VUS

LP

Meckel syndrome 1

MIM:249,000

8461

Increased echo in parenchyma of both kidneys, left hydronephrosis with extrarenal pelvis dilatation, polyhydramnios

Genitourinary system

HNF1B

NM_000458.4:

c.884G > A

p.(R295H)

AD

het (affected father)

LP

Renal cysts and diabetes

Syndrome

MIM:137,920

9445

Short limbs

Musculoskeletal system

COL11A2

NM_080680.3:

c.3850 C > T▲

p.(R1284W)

AD

de novo het

LP

Fibrochondrogenesis 2

MIM:614,524

1768

Curved femur, osteogenesis hypoplasia

Musculoskeletal system

COL1A1

NM_000088.4:

c.1084G > A

p.(G362S)

AD

het (affected father)

LP

Osteogenesis imperfecta

MIM:166,200

1781

Polydactyly in the left hand, polydactyly in both feet toes

Musculoskeletal system

GLI3

NM_000168.6:

c.868 C > T

p.(R290*)

AD

de novo het

P

Greig cephalopolysyndactyly syndrome

MIM:175,700

0602

Increased nuchal translucency (5.9 mm), intrauterine growth retardation

Other abnormalities of prenatal birth

RPS19

NM_001022.4:

c.3G > T

p.(M1?)

AD

de novo het

P

Diamond-Blackfan anemia 1

MIM:105,650

0646

Widen lateral ventricles, anterior horn hypoechoic, widen pellucid septum,

hypoplasia of corpus callosum

Nervous system

PDHA1

NM_000284.4:

c.766G > A▲

p.(G256R)

XLD

de novo het

LP

Pyruvate dehydrogenase E1-alpha deficiency

MIM:312,170

5588

Short femur, Short humerus, polyhydramnios

Musculoskeletal system

FGFR3

NM_000142.4:

c.1138G > A

p.(G380R)

AD

de novo het

P

Achondroplasia

MIM:100,800

5539

The left posterior frontal gyri was deepened and thicken the cerebral cortex

Multiple system

TSC2

NM_000548.5:

c.5238_5255del

p.(H1746_R1751

del)

AD

de novo het

P

Tuberous sclerosis-2

MIM:613,254

0543

Curved femur, short femur

Musculoskeletal system

COL1A1

NM_000088.4:

c.1678G > A

p.(G560S)

AD

de novo het

P

Osteogenesis imperfecta

MIM:166,200

Proband- only samples

3078

Short long bone

Musculoskeletal system

FGFR3

NM_000142.4:

c.1138G > A

p.(G380R)

AD

de novo het

P

Achondroplasia MIM:100,800

3031

Lethal short limb deformity, short limbs, small chest

Musculoskeletal system

FGFR3

NM_000142.4:

c.1108G > T

p.(G370C)

AD

de novo het

P

Thanatophoric dysplasia

MIM:187,600

3005

Hydrocephalus

Nervous system

L1CAM

NM_001278116.2:

c.2555del▲

p.(Y852Sfs*129)

XLR

hemi (unaffected mother)

LP

Hydrocephalus due to aqueductal stenosis

MIM:307,000

2919

Lethal short limb deformity, short fingers, small chest, lung dysplasia

Multiple system

FGFR3

NM_000142.4:

c.1118 A > G

p.(Y373C)

AD

de novo het

P

Thanatophoric dysplasia

MIM:187,600

4714

Short long bone, duplicate kidney, polyhydramnios

Multiple system

FGFR3

SOS1

NM_000142.4:

c.1138G > A

p.(G380R)

NM_005633.4:

c.1654 A > G

p.(R552G)

AD

AD

de novo het

de novo het

P

P

Achondroplasia

MIM:100,800

Noonan syndrome 4

MIM:610,733

8491

Left renal agenesis

Genitourinary system

GREB1L

NM_001142966.3:

c.4881_4882del

p.(H1627Qfs*17)

AD

de novo het

LP

Renal hypodysplasia/aplasia 3

MIM:617,805

1752

Increased nuchal translucency (6.8 mm), cystic hygroma, polyhydramnios

Other abnormalities of prenatal birth

RAF1

NM_002880.4:

c.770 C > T

p.(S257L)

AD

de novo het

P

Noonan syndrome 5

MIM:611,553

4743

Short femur, Short humerus, polyhydramnios

Musculoskeletal system

FGFR3

NM_000142.4:

c.1138G > A

p.(G380R)

AD

de novo het

P

Achondroplasia

MIM:100,800