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

Kolvenbach CM, Van Der Ven AT, Kause F, Shril S, Scala M, Connaughton DM, Mann N, Nakayama M, Dai R, Kitzler TM, Schneider R, Schierbaum L, Schneider S, Accogli A, Torella A, Piatelli G, Nigro V, Capra V, Hoppe B, Maerzheuser S, Schmiedeke E, Rehm HL, Mane S, Lifton RP, Dworschak GC, Hilger AC, Reutter HM, Hildebrandt F (2021)

Publication Type: Journal article

Publication year: 2021

Journal

American Journal of Medical Genetics Part A Wiley-Blackwell

DOI: 10.1002/ajmg.a.62447

Abstract

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.

Authors with CRIS profile

Heiko Martin Reutter

Involved external institutions

Harvard University US United States (USA) (US) University of Genova / Università degli Studi di Genova IT Italy (IT) Università degli studi della Campania Luigi Vanvitelli IT Italy (IT) Istituto Giannina Gaslini IT Italy (IT) Kindernierenzentrum Bonn DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) Klinikverbund Bremen (Gesundheit Nord) DE Germany (DE) Eli and Edythe L. Broad Institute of MIT and Harvard US United States (USA) (US) Yale University US United States (USA) (US) Universitätsklinikum Bonn DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE)

How to cite

APA:

Kolvenbach, C.M., Van Der Ven, A.T., Kause, F., Shril, S., Scala, M., Connaughton, D.M.,... Hildebrandt, F. (2021). Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes. American Journal of Medical Genetics Part A. https://doi.org/10.1002/ajmg.a.62447

MLA:

Kolvenbach, Caroline M., et al. "Exome survey of individuals affected by VATER/VACTERL with renal phenotypes identifies phenocopies and novel candidate genes." American Journal of Medical Genetics Part A (2021).

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