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Table 2 Patients with autosomal biallelically or X-linked inherited PTVs or Dmis variants in the 21 prioritized candidate genes

From: Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder

Gene

Proband (gender)

Type

Location (hg19)

Ref

Alt

GenBank No

Functional effect

Nucleotide change

AA. alteration

gnomAD allele frequency

pLI

Phenotypes in OMIM (Inheritance)

ACMG

Autosomal genes (n = 8)

 ANO5#

14,640.p1 (M)

Chet

chr11:22,242,756

G

A

NM_213599

SP/Syn

c.294G > A

SP/p.A98A

0.0007

0

Gnathodiaphyseal dysplasia (AD); Miyoshi muscular dystrophy 3 (AR); Muscular dystrophy, limb-girdle, autosomal recessive 12 (AR)

VUS

chr11: 22,294,441

C

G

NM_213599

Mis

c.2141C > G

p.T714S

0.0009

P

 ATAD3A*

14,517.p1 (M)

Chet

chr1:1,469,361

G

A

NM_001170535

Mis

c.1670G > A

p.R557H

0.0002

0

Harel-Yoon syndrome (AD, AR); Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (AR)

VUS

chr1:1,469,380

G

-

NM_001170535

FS

c.1689delG

p.Q563Hfs*9

0

P

 ATG7

13,998.p1 (M)

Chet

chr3:11,389,351

G

T

NM_006395

SP/Mis

c.1126G > T

SP/p.G376C

5.58E-05

0

 

VUS

chr3:11,404,365

G

A

NM_006395

Mis

c.1762G > A

p.V588M

0.0001

 

VUS

 HIPK3

13,076.p1 (M)

Homo

chr11:33,374,639

T

C

NM_001048200

SP/Mis

c.3110 T > C

SP/p.V1037A

0.0008

0.28

 

VUS

I NTS4

14,051.p1 (M)

Chet

chr11:77,635,920

G

A

NM_033547

SG

c.1390C > T

p.R464X

1.23E-05

0

 

VUS

chr11:77,649,828

G

A

NM_033547

Mis

c.1034C > T

p.S345L

0.0004

 

VUS

 LLGL1

14,404.p1 (M)

Homo

chr17:18,138,154

G

A

NM_004140

SP/Mis

c.907G > A

SP/p.G303S

0.0009

0

 

VUS

 RFT1*

11,176.p1 (M)

Chet

chr3:53,133,472

T

C

NM_052859

Mis

c.1133A > G

p.Y378C

0.0005

0

Congenital disorder of glycosylation (AR)

VUS

chr3:53,126,384

C

–

NM_052859

SP

c.1458 + 1G > -

SP

4.53E-06

P

 VPS13B*

12,651.p1 (M)

Chet

chr8:100,829,780

G

A

NM_017890

Mis

c.8185G > A

p.G2729R

7.98E-06

0

Cohen syndrome (AR)

LP

chr8:100,396,500

G

A

NM_017890

SG

c.2889G > A

p.W963X

0

P

X-linked genes (n = 13)

 AFF2*

14,096.p1 (M)

Hem

chrX:148,068,931

-

C

NM_001170628

FS

c.2582dupC

p.I863Hfs*6

0

1

Mental retardation, X-linked, FRAXE type (XLR)

P

 APOO

14,187.p1 (M)

Hem

chrX:23,886,804

G

A

NM_024122

SP/Syn

c.294C > T

SP/p.D98D

0

0.6

 

VUS

 CCDC22*

12,325.p1 (M)

Hem

chrX:49,105,278

A

C

NM_014008

SP/Mis

c.1432A > C

SP/p.M478L

0

1

Ritscher-Schinzel syndrome 2 (XLR)

LP

11,720.p1 (M)

chrX:49,105,359

C

T

NM_014008

Mis

c.1513C > T

p.R505W

6.18E-05

LP

 CUL4B*

14,363.p1 (M)

Hem

chrX:119,708,407

A

G

NM_003588

SP/Syn

c.66 T > C

SP/p.G22G

0

1

Mental retardation, syndromic 15 (XLR)

LP

 CYBB#

14,070.p1 (M)

Hem

chrX:37,664,420

A

G

NM_000397

SP/Mis

c.1313A > G

SP/p.K438R

4.39E-05

1

Chronic granulomatous disease, X linked (XLR); Immunodeficiency 34, mycobacteriosis (XLR)

LP

 GRIPAP1

14,524.p1 (M)

Hem

chrX:48,837,828

C

T

NM_020137

SP/Syn

c.1830G > A

SP/p.A610A

0.0001

1

 

VUS

 HDAC8*

13,136.p1 (M)

Hem

chrX:71,694,562

G

-

NM_001166419

FS

c.755delC

p.P252Qfs

7.35E-05

0.98

Cornelia de Lange syndrome 5 (XLD)

LP

 IL13RA1

11,167.p1 (M)

Hem

chrX:117,881,009

T

G

NM_001560

Mis

c.321 T > G

p.S107R

0

0.96

 

VUS

11,488.p1 (M)

chrX:117,895,252

C

T

NM_001560

SP/Syn

c.828C > T

SP/p.Y276Y

2.48E-05

 

VUS

 MED12*

11,217.p1 (M)

Hem

chrX:70,343,445

G

A

NM_005120

SP/Mis

c.1619G > A

SP/p.R540H

1.33E-05

1

Lujan-Fryns syndrome (XLR), Ohdo syndrome(XLR), Opitz-Kaveggia syndrome (XLR)

VUS

12,626.p1 (M)

chrX:70,352,298

A

G

NM_005120

Mis

c.4325A > G

p.H1442R

0

LP

 RBMX*

13,063.p1 (M)

Hem

chrX:135,957,417

C

T

NM_002139

SP/Mis

c.782G > A

SP/p.S261N

0

0.83

Mental retardation, X-linked, syndromic 11, Shashi type (XLR)

LP

 SLC38A5

14,423.p1 (M)

Hem

chrX:48,325,258

C

T

NM_033518

SP/Mis

c.247G > A

SP/p.A83T

0

0.98

 

VUS

 UBE2A*

12,440.p1 (M)

Hem

chrX:118,716,638

A

T

NM_003336

SP/Mis

c.329A > T

SP/p.Q110L

0

0.82

Mental retardation, X-linked syndromic, Nascimento-type (XLR)

LP

 USP9X*

13,929.p1 (M)

Hem

chrX:40,982,891

A

G

NM_001039590

Mis

c.10A > G

p.T4A

1.52E-05

1

Mental retardation, X-linked 99(XLR); Mental retardation, X-linked 99, syndromic, female-restricted (XLD)

LP

11,358.p1 (M)

chrX:40,996,058

G

A

NM_001039590

SP/Mis

c.437G > A

SP/p.R146K

0

LP

12,628.p1 (M)

chrX:41,012,318

G

C

NM_001039590

Mis

c.1881G > C

p.M627I

1.39E-05

LP

  1. Genes marked with * are implicated in neurodevelopmental disorders, and those marked with # are associated with other genetic disorders. The coding variants within ± 2 bp of the exon–intron boundary were defined as cryptic splice sites using ANNOVAR. All X-linked hemizygous inherited variants were analyzed in males. The reference sequence of a certain gene in the ClinVar database or the transcript with the highest expression in the human brain based on the GTEx database was selected to annotate the recessive inherited variants. AD, autosomal dominant; AR, autosomal recessive; Chet, compound heterozygous; Dmis, deleterious missense; F, female; FS, frameshift; Hem, hemizygous; Homo, homozygous; LP, likely pathogenic; M, male; Mis, missense; P, pathogenic; pLI, probability of loss-of-function intolerance; PTVs, protein-truncating variants; SG, stop-gain; SP, splicing; Syn, synonymous; XLD, X-linked dominant; XLR, X-linked recessive; VUS, variant of uncertain significance. The variants in known disease genes were interpreted according to ACMG guidelines and other variants were determined as VUSs. The variants in VPS13B were reported in a previous study [37]