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Abstract: FR-PO793

Whole-Exome Sequencing in 33 Families with VACTERL or VACTERL-Like Phenotype Identifies Potential New Candidate Genes

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Kolvenbach, Caroline M., Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Van der ven, Amelie, Boston Children's Hospital, Harvard Medical School, Boston, United States
  • Kause, Franziska, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Connaughton, Dervla M., Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Mann, Nina, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Nakayama, Makiko, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Dai, Rufeng, Boston Children's Hospital/Children's Hospital of Fudan University, Boston, Massachusetts, United States
  • Dworschak, Gabriel C., University of Bonn, Children's Hospital, Bonn, NRW, Germany
  • Hilger, Alina, University of Bonn, Children's Hospital, Bonn, NRW, Germany
  • Reutter, Heiko M., University of Bonn, Children's Hospital, Bonn, NRW, Germany
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

VACTERL association describes the combination of congenital anomalies including vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Involvement of genetic factors in its pathogenesis is supported by reports of familial segregation, but only four likely monogenic causes have been suggested (FOXF1, HOXD13, PTEN, ZIC3).

Methods

We performed unbiased whole exome sequencing (WES) to identify monogenic or digenic causes in 33 families with VACTERL or VACTERL-like phenotype.

Results

We evaluated the WES data for causative mutations in 3 different groups of known or candidate VACTERL genes: i) mutations in the 4 known VACTERL genes FOXF1, HOXD13, PTEN and ZIC3, ii) in 108 VACTERL candidate genes of the Shh or Wnt pathway, and iii) in 58 syndromic human CAKUT genes. In addition, we evaluated WES data for mutations in potential novel VACTERL genes under 5 different monogenic hypotheses: iv) recessive, v) dominant, vi) de novo, vii) digenic dominant or viii) digenic recessive mutations. We detected no mutation in any of the 4 known VACTERL genes (above group i). In group ii we detected potential mutations in 11 different genes. In group iii we detected potential mutations in 13 genes. When evaluating for potential novel VACTERL genes, we identified recessive (group iv, n=4, B9D1, CORO7, TTLL11, NKX2-3), dominant (group v, n=5), de novo (group vi, n=1), digenic dominant (group vii, n=11) and digenic recessive mutations (group viii, n=3). Overall, we detected mutations in 25/33 families in 44 genes (17 had more than one potential gene). Interestingly, in 7 individuals at least one mutation in a known gene for syndromic CAKUT together with a second mutation in another syndromic CAKUT or VACTERL candidate gene could be found. Array-based molecular karyotyping revealed no copy number variants in any of the 33 families.

Conclusion

This study establishes that WES can identify mutations in potential candidate genes in 76% of families with VACTERL or VACTERL-like phenotype. Furthermore, WES shows a potential digenic mode of inheritance in 51% of our cohort.