Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes
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Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes. / Kolvenbach, Caroline M; van der Ven, Amelie T; Kause, Franziska; Shril, Shirlee; Scala, Marcello; Connaughton, Dervla M; Mann, Nina; Nakayama, Makiko; Dai, Rufeng; Kitzler, Thomas M; Schneider, Ronen; Schierbaum, Luca; Schneider, Sophia; Accogli, Andrea; Torella, Annalaura; Piatelli, Gianluca; Nigro, Vincenzo; Capra, Valeria; Hoppe, Bernd; Märzheuser, Stefanie; Schmiedeke, Eberhard; Rehm, Heidi L; Mane, Shrikant; Lifton, Richard P; Dworschak, Gabriel C; Hilger, Alina C; Reutter, Heiko; Hildebrandt, Friedhelm.
In: AM J MED GENET A, Vol. 185, No. 12, 12.2021, p. 3784-3792.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -