Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes

TY - JOUR

T1 - Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes

AU - Kolvenbach, Caroline M

AU - van der Ven, Amelie T

AU - Kause, Franziska

AU - Shril, Shirlee

AU - Scala, Marcello

AU - Connaughton, Dervla M

AU - Mann, Nina

AU - Nakayama, Makiko

AU - Dai, Rufeng

AU - Kitzler, Thomas M

AU - Schneider, Ronen

AU - Schierbaum, Luca

AU - Schneider, Sophia

AU - Accogli, Andrea

AU - Torella, Annalaura

AU - Piatelli, Gianluca

AU - Nigro, Vincenzo

AU - Capra, Valeria

AU - Hoppe, Bernd

AU - Märzheuser, Stefanie

AU - Schmiedeke, Eberhard

AU - Rehm, Heidi L

AU - Mane, Shrikant

AU - Lifton, Richard P

AU - Dworschak, Gabriel C

AU - Hilger, Alina C

AU - Reutter, Heiko

AU - Hildebrandt, Friedhelm

N1 - © 2021 Wiley Periodicals LLC.

PY - 2021/12

Y1 - 2021/12

N2 - The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis, the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL-like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN, and ZIC3 have been associated with the VATER/VACTERL association; however, large-scale re-sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL-like phenotype to identify potentially novel genetic causes. Exome analysis identified biallelic and X-chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. Our study suggests six biallelic and X-chromosomal hemizygous VATER/VACTERL disease genes implicating all six genes in the expression of human renal malformations.

AB - The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac anomalies (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb anomalies (L). For the clinical diagnosis, the presence of at least three CFs is required, individuals presenting with only two CFs have been categorized as VATER/VACTERL-like. The majority of VATER/VACTERL individuals displays a renal phenotype. Hitherto, variants in FGF8, FOXF1, HOXD13, LPP, TRAP1, PTEN, and ZIC3 have been associated with the VATER/VACTERL association; however, large-scale re-sequencing could only confirm TRAP1 and ZIC3 as VATER/VACTERL disease genes, both associated with a renal phenotype. In this study, we performed exome sequencing in 21 individuals and their families with a renal VATER/VACTERL or VATER/VACTERL-like phenotype to identify potentially novel genetic causes. Exome analysis identified biallelic and X-chromosomal hemizygous potentially pathogenic variants in six individuals (29%) in B9D1, FREM1, ZNF157, SP8, ACOT9, and TTLL11, respectively. The online tool GeneMatcher revealed another individual with a variant in ZNF157. Our study suggests six biallelic and X-chromosomal hemizygous VATER/VACTERL disease genes implicating all six genes in the expression of human renal malformations.

U2 - 10.1002/ajmg.a.62447

DO - 10.1002/ajmg.a.62447

M3 - SCORING: Journal article

C2 - 34338422

VL - 185

SP - 3784

EP - 3792

JO - AM J MED GENET A

JF - AM J MED GENET A

SN - 1552-4825

IS - 12

ER -