Re‐sequencing of candidate genes FOXF1, HSPA6, HAAO, and KYNU in 522 individuals with VATER/VACTERL, VACTER/VACTERL‐like association, and isolated anorectal malformation

Abstract

Background The acronym VATER/VACTERL association describes the combination of at least three 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). Individuals presenting two CFs have been termed VATER/VACTERL‐like. Recently, FOXF1, HSPA6, HAAO, KYNU, TRAP1, and ZIC3 have been proposed as candidate genes for VATER/VACTERL, VATER/VACTERL‐like, and ARM. Re‐sequencing studies identified disease‐causing variants in TRAP1 and ZIC3, the contribution of other genes was not independently investigated. One affected variant carrier in FOXF1 was previously identified. Here we re‐sequenced FOXF1, HSPA6, HAAO, and KYNU in 522 affected individuals. Methods Using molecular inversion probe (MIP) technology, re‐sequencing was performed in 63 individuals with VATER/VACTERL association, 313 with VATER/VACTERL‐like association, and 146 with ARM. All individuals were of European ethnicity. Variant filtering considered variants with a minor allele frequency (MAF) ≤0.01 for putative recessive disease‐genes HSPA6, HAAO, and KYNU. For the putative dominant disease‐gene FOXF1 we considered variants with a MAF ≤0.0001. In silico prediction tools were used for further prioritization. Results Only two variants in FOXF1 in two independently affected individuals [c.443G>T, p.(Cys148Phe); c.850T>C, p.(Tyr284His)] passed our filter criteria. One individual presented with ARM, the second presented with TE and C comprising atrial and ventricular septal defects. Sanger sequencing confirmed both variants but also their inheritance from the healthy mother. Conclusion Our analysis suggests that FOXF1, HSPA6, HAAO and KYNU do not play a major role in the formation of VACTER/VACTERL phenotypes or ARM.

Updated EUROCAT guidelines for classification of cases with congenital anomalies

“…In step 2, all cases with a teratogenic syndrome code and at least one other accepted major anomaly code will be transferred to group T—the teratogenic syndrome group. In step 3 (newly added), cases with a code for the VACTERL association or oculo‐auriculo‐vertebral spectrum (OAVS, Goldenhar) will be transferred to group M. The underlying reason for transferring OAVS and VACTERL to group M is that in both conditions multiple congenital anomalies are present and the underlying cause remains unknown in the majority of cases (Bogusiak et al, 2017; Thiem et al, 2022; van de Putte et al, 2020). Group M is the group with potential MCA.…”

Tracheal agenesis versus tracheal atresia: anatomical conditions, pathomechanisms and causes with a possible link to a novel MAPK11 variant in one case

“…Unfortunately, we could not sequence the FFPE-DNA of case 2 in order to verify or exclude a MAPK11 variant in our second child with isolated TAG. The lack of evidence of a pathogenic gene variant in our TAG cases 3 to 5 with accompanying VACTERL features may indicate that TAG is part of the VACTERL specific characteristics, a clinical picture affecting different developmental fields at different developmental periods for which no potential teratogenic or genetic alteration common to the majority of cases has yet been identified [ 41 – 43 ].…”

Ear anomalies and hearing loss in patients with VACTERL association and the effect of maternal diabetes

“…Despite significant advancements in genomics research, the underlying causes of this condition have remained elusive. Only a small proportion of patients have a confirmed genetic etiology (Thiem et al, 2022), while the etiology remains unknown in most cases. It is likely that environmental factors and gene–environment interactions play a role in pathogenesis (Solomon, 2018; Stevenson & Hunter, 2013; van de Putte et al, 2020).…”