HSPA6: A new autosomal recessive candidate gene for the VATER/VACTERL malformation spectrum.
Abnormalities, Multiple
/ genetics
Alleles
Anal Canal
/ abnormalities
Anorectal Malformations
/ genetics
Anus, Imperforate
/ diagnosis
Esophageal Atresia
Esophagus
/ abnormalities
Exome
Female
HSP70 Heat-Shock Proteins
/ genetics
HSP90 Heat-Shock Proteins
/ genetics
Heart Defects, Congenital
/ diagnosis
Humans
Kidney
/ abnormalities
Limb Deformities, Congenital
/ diagnosis
Male
Mutation
Phenotype
Radius
/ abnormalities
Siblings
Spine
/ abnormalities
Trachea
/ abnormalities
Tracheoesophageal Fistula
HSPA6
VATER/VACTERL association
anorectal malformations
autosomal recessive inheritance
whole-exome sequencing
Journal
Birth defects research
ISSN: 2472-1727
Titre abrégé: Birth Defects Res
Pays: United States
ID NLM: 101701004
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
30
12
2018
revised:
21
02
2019
accepted:
03
03
2019
pubmed:
20
3
2019
medline:
24
3
2020
entrez:
20
3
2019
Statut:
ppublish
Résumé
The VATER/VACTERL association refers to the nonrandom co-occurrence of at least three of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Patients presenting with two CFs have been termed VATER/VACTERL-like phenotypes. We surveyed the exome for recessive disease variants in three affected sib-pairs. Sib-pair 971 consisted of two brothers with ARM and additional hydronephrosis in one brother. Sib-pair 1098 consisted of two sisters with ARM. In family 1346, the daughter presented with ARM and additional hypoplasia of both small fingers and ankyloses. Her brother presented with unilateral isolated radial hypoplasia. Sib-pairs 971 and 1346 resembled a VATER/VACTERL-like phenotype. We detected a novel maternally inherited missense variant (c.1340G > T) and a rare paternally inherited deletion of the trans-allele in HSPA6 in both siblings of family 1346. HSPA6 belongs to the heat shock protein (HSP) 70 family. Re-sequencing of HSPA6 in 167 patients with VATER/VACTERL and VATER/VACTERL-like phenotypes did not reveal any additional bi-allelic variants. Until now, only TNF-receptor associated protein 1 (TRAP1) had been reported as an autosomal recessive disease-gene for the VATER/VACTERL association. TRAP1 belongs to the heat shock protein 90 family (HSP90). Both Hsp70 and Hsp90 genes have been shown to be important embryonic drivers in the formation of mouse embryonic forelimb tissue. Our results suggest HSPA6 as a new candidate gene in VATER/VACTERL-like phenotypes.
Sections du résumé
BACKGROUND
The VATER/VACTERL association refers to the nonrandom co-occurrence of at least three of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Patients presenting with two CFs have been termed VATER/VACTERL-like phenotypes.
METHODS
We surveyed the exome for recessive disease variants in three affected sib-pairs. Sib-pair 971 consisted of two brothers with ARM and additional hydronephrosis in one brother. Sib-pair 1098 consisted of two sisters with ARM. In family 1346, the daughter presented with ARM and additional hypoplasia of both small fingers and ankyloses. Her brother presented with unilateral isolated radial hypoplasia. Sib-pairs 971 and 1346 resembled a VATER/VACTERL-like phenotype.
RESULTS
We detected a novel maternally inherited missense variant (c.1340G > T) and a rare paternally inherited deletion of the trans-allele in HSPA6 in both siblings of family 1346. HSPA6 belongs to the heat shock protein (HSP) 70 family. Re-sequencing of HSPA6 in 167 patients with VATER/VACTERL and VATER/VACTERL-like phenotypes did not reveal any additional bi-allelic variants.
CONCLUSIONS
Until now, only TNF-receptor associated protein 1 (TRAP1) had been reported as an autosomal recessive disease-gene for the VATER/VACTERL association. TRAP1 belongs to the heat shock protein 90 family (HSP90). Both Hsp70 and Hsp90 genes have been shown to be important embryonic drivers in the formation of mouse embryonic forelimb tissue. Our results suggest HSPA6 as a new candidate gene in VATER/VACTERL-like phenotypes.
Identifiants
pubmed: 30887706
doi: 10.1002/bdr2.1493
pmc: PMC6662190
mid: NIHMS1016274
doi:
Substances chimiques
HSP70 Heat-Shock Proteins
0
HSP90 Heat-Shock Proteins
0
HSPA6 protein, human
0
TRAP1 protein, human
0
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
591-597Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK076683
Pays : United States
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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