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Table 1 Overview of the families and variants identified by targeted next-generation sequencing analysis and exome sequencing

From: Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders

Family ID

Consanguinity

Phenotype in the deceased child and DD

Number/gender/age of lost child/miscarriage

Gene (OMIM)

Variant identified in the couples

Variant confirmed in deceased child

CADD/Classification of variant

Disease (OMIM)

Increased risk for autosomal recessive disorder

spontaneous pregnancy with prenatal diagnosis

PGD

1

yes

intrauterine epilepsy, severe brain malformation

DD: early epileptic encephalopathy

3 m + f

neonatal

CTSD (*116840)

FTCD (*606806)

NM_001909: c.268_269insC p.(Gln90Profs*50) mat and pat het

NM_001320412: c.530G > A p.(Gly177Glu)

mat and pat het

CTSD: hom

CADD: n.a./Class 4

CADD: 25.8/Class 4

Ceroid lipofuscinosis,

type 10 (#610127)

Glutamate formiminotransferase deficiency (#229100)

two, CVS: CTSD: het

FTCD: wt and het

planned

2

no

severe congenital lactic acidosis

DD: pyruvate dehydrogenase deficiency

1 f

neonatal

COQ2 (*609825)

mother: NM_015697: c.1197delT p.(Asn401Ilefs*15)

father: c.764C > T p.(P255L)

no

CADD: 23.7/Class 5

CADD: 29/

Class 4

Coenzyme Q10 deficiency, primary, type 1 (#607426)

yes, AC:

COQ2: comp het

in progress

3

yes

SIDS, severe hypertrophic cardiomyopathy

DD: FAOD, primary carnitine deficiency

1 m 5 months

1 MC

ACADVL (*609575)

NM_001033859: c.1274 T > C, p.(L425P)

mat and pat het

ACADVL : hom

CADD: 27.4/Class 4

VLCAD deficiency, (#201475)

no

planned

4

yes

hyperinflammatory syndrome with hepatosplenomegaly, suspicion of hemophagocytic lymphohistiocytosis

DD: PID

1f

neonatal

3 MC

UNC13D (*608897)

NM_199242: c.2447 + 1G, p.? donor site change)

mat and pat het

no

CADD: 27.4/Class 4

Familial hemophagocytic lymphohistiocytosis type 3 (#608898)

no

planned

5

yes

spasticity, muscular hypotonia, epileptic encephalopathy, optic atrophy

DD: Leigh syndrome, Pelizeus-Merzbacher syndrome

1 m

11 months

BRAT1 (*614506)

NM_152743: c. 1280G > A p.(Arg427Gln)

mat and pat het

no

CADD: 32/

Class 4

Rigidity and multifocal seizure syndrome (#614498)

prenatal diagnostics declined

planned

6

no

severe muscular hypotonia, respiratory insufficiency, seizures

DD: mitochondriopathy

1 f

16 months

1 MC

 

none

   

yes: no prenatal diagnostics,

healthy child

no

7

yes

severe lissencephaly type 2

1 f, 2 m

neonatal

PALLD (*608092)

NM_001166108: Exon 1 deletion mat and pat het

PALLD : hom

CADD: n.a./

Class 3

No OMIM disease entry

mouse: migration defect [17]

no

planned

8

yes

dilated cardiomyopathy, congenital myopathy

DD: mitochondriopathy

1 f

5 months

1 MC

none

none

no

  

yes: no prenatal diagnostics: healthy child

no

9

no

1: meningocele, hydrocephalus

2: intracerebral hemorrhage, respiratory insufficiency

DD: exogenous factors

1 m

neonatal

1 f neonatal

1 MC

none

none

no

  

no

no

10

yes

3 miscarriages with ascites, cardiomegaly, skeletal deformity, biochemical suspicion of mucolipidosis type II

4 MC (f + m)

none

none

no

  

no

no

11

no

early-onset severe epilepsy

DD: infantile epileptic encephalopathies

1 f, 2 m

16–21 months

none

none

no

  

no

no

12

yes

microcephaly, IUGR, cerebellar hypoplasia, rockerbottom feet, hydronephrosis

1 f

6 months

3 MC

none

none

no

  

no

no

13

no

anencephaly, iu lethal

DD: folate deficiency

2 MC

11th week of gestation

APAF1 (*602233)

mother: NM_181861: c.1350C > G p.(Cys450Trp)

father: c.3127C > G p.(His1043Asp)

APAF1 : comp het

CADD: 23.1/Class 3

CADD: 25.7/

Class 3

No OMIM disease entry

mouse model: anencephaly, neurogenesis defect [20]

no

planned

  1. Abbreviations: iu intrauterine, f female, m male, MC miscarriage, het heterozygous, hom homozygous, comp het compound heterozygous, no: no material available for study, DD differential diagnosis, CADD score combined annotation dependent depletion framework, PGD preimplantation genetic diagnosis, PID primary immunodeficiency, FAOD fatty acid oxidation defect
  2. likely or possibly causative variants and the corresponding disease in the couples are highlighted in boldface