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Table 3 Deleterious sequence variants identified in patients with ASD in day-care hospitals of the Greater Paris region

From: Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder

Patient

Method

Gene

Reference sequence

cDNA and protein changes

Zygosity

Mode of inheritance

Sex

ACMG classificationa

Evidence

Phenotype (MIM number)

35

ASD/ID panel

ADNP

NM_015339

c.2499del, p.Val834Serfs*80

Heterozygous

De novo

M

Pathogenic (Ia)

PVS1, PS2, PM2

Helsmoortel van der Aa syndrome (615873)

36

ASD/ID panel

ADNP

NM_015339

c.517C>T, p.Arg173*

Heterozygous

De novo

M

Pathogenic (Ia)

PVS1, PS2, PM2

Helsmoortel van der Aa syndrome (615873)

37

ASD/ID panel

ANKRD11

NM_013275

c.3542_3543ins23, p.Arg1182Alafs*144

Heterozygous

De novo

M

Pathogenic (Ia)

PVS1, PS2, PM2

KBG syndrome (148050)

38

ASD/ID panel

ARID1B

NM_020732.3

c.4110G>A, p.His1339Ilefs*77 (b)

Heterozygous

De novo

M

Pathogenic (Ia)

PVS1, PS2, PS1, PM2

Coffin-Siris syndrome 1 (135900)

39

WES

ATRX

NM_000489.3

c.6740A>C, p.His2247Pro

Hemizygous

Inherited from heterozygous mother

M

Likely pathogenic (II)

PS1, PM2, PP2, PP3, PP4

Mental retardation-hypotonic facies syndrome, X-linked (309580)

40

WES

CACNA1E

NM_000721.3

c.4688A>G, p.Lys1563Arg

Heterozygous

De novo

M

Likely pathogenic (II)

PS2, PM2, PP2, PP3

Epileptic encephalopathy, early infantile, 69 (618285)

41

WES

CHD2

NM_001271.3

c.2352+1G>A, p.Lys730Asnfs*4 Skip of exon 18

Heterozygous

De novo

M

Pathogenic (Ia)

PVS1, PS2, PM2

Epileptic encephalopathy, childhood-onset (615369)

42

WES

COG4

NM_015386.2

c.15G>A, p.Met5Ile

Homozygous

Inherited from heterozygous parents

M

Likely pathogenic (V)

PM2, PM3, PP2, PP3, PP4

Congenital disorder of glycosylation, type IIj (613489)

43

WES

FOXP1

NM_032682.5

c.1541G>A, p.Arg514His

Heterozygous

De novo

F

Likely pathogenic (II)

PS2, PM2, PP2, PP3

Mental retardation with language impairment and with or without autistic features (613670)

44

ASD/ID panel

FOXP1

NM_032682.5

c.1541G>A, p.Arg514His

Heterozygous

De novo

F

Likely pathogenic (II)

PS2, PM2, PP2, PP3

Mental retardation with language impairment and with or without autistic features (613670)

45

WES

GNAO1

NM_020988.2

c.736G>A, p.Glu246Lys

Heterozygous

De novo

F

Pathogenic (II)

PS2, PS1, PM2, PP2, PP3, PP4

Epileptic encephalopathy, early infantile 17 (615473)

46c

ASD/ID panel

GRIA3

NM_000828

c.504del, p.Glu168Aspfs*21

Hemizygous

Inherited from mother with somatic mosaicism

M

Pathogenic (Ib)

PVS1, PM2, PP1-M

Mental retardation, X-linked 94 (300699)

47c

ASD/ID panel

GRIA3

NM_000828

c.504del, p.Glu168Aspfs*21

Hemizygous

Inherited from mother with somatic mosaicism

M

Pathogenic (Ib)

PVS1, PM2, PP1-M

Mental retardation, X-linked 94 (300699)

48

ASD/ID panel

GRIA3

NM_000828

c.1990C>G, p.Pro664Ala

Hemizygous

Inherited from heterozygous mother

M

Likely pathogenic (II)

PS1, PM2, PP2, PP3, PP4

Mental retardation, X-linked 94 (300699)

49

ASD/ID panel

GRIN2B

NM_000834.4

c.2087G>A, p.Arg696His

Heterozygous

De novo

F

Pathogenic (II)

PS2, PS1, PM2, PP2, PP3, PP4

Mental retardation, autosomal dominant 6 (613970)

50

ASD/ID panel

GRIN2B

NM_000834.4

c.2084T>C, p.Ile695Thr

Heterozygous

De novo

M

Pathogenic (II)

PS2, PS1, PM2, PP2, PP3, PP4

Mental retardation, autosomal dominant 6 (613970)

51

ASD/ID panel

HUWE1

NM_031407.6

c.1736A>C, p.Asn579Thr

Hemizygous

Inherited from heterozygous mother

M

Likely pathogenic (II)

PS1, PM2, PP2, PP3, PP4

Mental retardation, X-linked syndromic (300706)

52

Epilepsy panel

IQSEC2

NM_001111125.2

c.2272C>T, p.Arg758*

Heterozygous

de novo

F

Pathogenic (Ia)

PVS1, PS2, PM2

Mental retardation, X-linked 78 (309530)

53

WES

KCNB1

NM_004975.2

c.128A>G, p.Glu43Gly

Heterozygous

De novo

M

Likely pathogenic (II)

PS2, PM2, PP3, PP2

Epileptic encephalopathy, early infantile 26 (616056)

54

ASD/ID panel

KDM6A

NM_021140.3

c.2944G>T, p.Gly982*

Heterozygous

De novo

M

Pathogenic (Ia)

PVS1, PS2, PM2

Kabuki syndrome 2 (300867)

55

WES

LINS1

NM_001040616.2

c.1921del, p.Glu641Serfs*4

Homozygous

Inherited from heterozygous parents

M

Likely pathogenic (V)

PM2, PM3, PP2, PP3, PP4

Mental retardation, autosomal recessive 27 (614340)

56

ASD/ID panel

MED13L

NM_015335.4

c.1708_1709del, p.Ser570Phefs*27

Heterozygous

De novo

F

Pathogenic (Ia)

PVS1, PS2, PM2

Mental retardation and distinctive facial features with or without cardiac defects (616789)

57

ASD/ID panel

MYT1L

NM_015025.3

c.1579G>C, p.Gly527Arg

Heterozygous

De novo

F

Pathogenic (II)

PS2, PS1, PM2, PP2, PP3, PP4

Mental retardation, autosomal dominant 39 (616521)

58

ASD/ID panel

NAA10

NM_003491.3

c.236G>A, p.Arg79His

Heterozygous

De novo

M

Likely pathogenic (II)

PS2, PM2, PP2, PP3

Ogden syndrome (300855)

59

WES

PHF6

NM_032458.2

c.385C>T, p.Arg129*

Heterozygous

De novo

F

Pathogenic (Ia)

PVS1, PS2, PM2

Borjeson-Forssman-Lehmann syndrome (301900)

60

WES, Epilepsy panel

RORB

NM_006914.3

c.640C>T, p.Arg214*

Heterozygous

De novo

F

Pathogenic (Ia)

PVS1, PS2, PM2

Epilepsy, idiopathic generalized, susceptibility to, 15 (618357)

61

ASD/ID panel

SHANK3

NM_033517.1

c.5021G>A, p.Gly1674Asp

Heterozygous

Inherited from the affected mother

M

Likely pathogenic (II)

PP1-S, PM2, PP2, PP3, PP4

Phelan-McDermid syndrome (606232)

62

ASD/ID panel

SHANK3

NM_033517.1

c.3679dup, p.(Ala1227Glyfs*69)

Heterozygous

De novo

M

Pathogenic (Ia)

PVS1, PS2, PM2

Phelan-McDermid syndrome (606232)

63

ASD/ID panel

SLC6A1

NM_003042

c.752T>C, p.Leu251Pro

Heterozygous

De novo

F

Likely pathogenic (II)

PS2, PM2, PP3, PP2

Myoclonic-atonic epilepsy (616421)

64

Epilepsy panel

STXBP1

NM_003165.3

c.87+1G>T, p.?

Heterozygous

De novo

M

Pathogenic (Ia)

PVS1, PS2, PM2

Epileptic encephalopathy, early infantile, 4 (612164)

65

ASD/ID panel

SZT2

NM_015284.3

c.1261+1G>A, p.? c.6113A>G, p.Tyr2038Cys

Compound heterozygous

Inherited from heterozygous parents

F

Likely pathogenic (V)

PVS1, PM2, PM3, PP2, PP3, PP4

Epileptic encephalopathy, early infantile 18 (615476)

66

ASD/ID panel

TLK2

NM_006852.3

c.1015C>T, p.Arg339Trp

Heterozygous

De novo

M

Pathogenic (II)

PS2, PS1, PM2, PP2, PP3, PP4

Mental retardation, autosomal dominant 57 (618050)

67

WES

TUSC3

NM_006765.3

c.787_788insC, p.Asn263Thrfs*

homozygous

Inherited from heterozygous parents

M

Pathogenic (Ib)

PVS1, PM2, PM3, PP2

Mental retardation, autosomal recessive 7 (611093)

  1. ASD autism spectrum disorder, F female, ID intellectual disability, M male, WES whole exome sequencing
  2. aVariants were assessed for pathogenicity according to the American College of Medical Genetics and Genomics (ACMG) criteria [7]
  3. bIn patient 38, the c.4110G>A variant in ARID1B is predicted to result in a synonymous substitution (p.Pro1370=) in the last base pair of exon 17. Further studies indicated that this variant affects the splice donor site and induces skipping of exon 17, causing a frameshift and premature termination (p.His1339Ilefs*77) [16]
  4. cPatients 46 and 47 are siblings