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

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.

Keywords: VATER/VACTERL association; anorectal malformation (ARM); congenital anomalies of the kidneys and urinary tract (CAKUT); exome sequencing (WES); monogenic disease causation.

Figure 1.. Number and percentage of 21 VATER/VACTERL families in whom a potential causative variant was detected by WES.

Purple color denotes the fraction of families with a variant in a causative gene assumed to phenocopy the VATER/VACTERL phenotype. Red denotes a variant in a potential novel monogenic candidate gene resulting from WES was identified. Yellow denotes the fraction of families if no variant could be derived from WES. (A) In 2 of 21 families with a VATER/VACTERL phenotype (10%), variants were detected in genes (B9D1 and FREM1) phenocopying the VATER/VACTERL features (purple). (B) In 4 of 21 families (19%), a single potential novel candidate gene (ZNF157, SP8, ACOT9, and TTLL11) for VATER/VACTERL could be identified per family (red). (C) In 15 of 21 families (71%), no variant was detected (yellow).