. 2022 Jun;114(10):478-486.

doi: 10.1002/bdr2.2008. Epub 2022 Mar 31.

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

Corina E Thiem¹, Jil D Stegmann^{1

2}, Alina C Hilger^{1

3

4}, Lea Waffenschmidt¹, Charlotte Bendixen^{1

5}, Ricarda Köllges¹, Eberhard Schmiedeke⁶, Frank-Mattias Schäfer⁷, Martin Lacher⁸, Ferdinand Kosch⁹, Sabine Grasshoff-Derr¹⁰, Carmen Kabs¹¹, Jörg Neser¹², Ekkehart Jenetzky^{13

14}, Julia Fazaal¹, Johannes Schumacher¹⁵, Julia Hoefele¹⁶, Kerstin U Ludwig¹, Heiko Reutter^{1

17}

Affiliations

¹ Institute of Human Genetics, Medical Faculty of the University Bonn & University Hospital Bonn, Bonn, Germany.
² Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany.
³ Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
⁴ Research Center On Rare Kidney Diseases (RECORD), University Hospital Erlangen, Erlangen, Germany.
⁵ Department of General, Visceral, Vascular and Thoracic Surgery, Unit of Pediatric Surgery, University Hospital Bonn, Bonn, Germany.
⁶ Clinic for Paediatric Surgery and Paediatric Urology, Klinikum Bremen-Mitte, Bremen, Germany.
⁷ Department of Pediatric Surgery and Urology, Cnopf'sche Kinderklinik, Nürnberg, Germany.
⁸ Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany.
⁹ Department of Pediatric Surgery, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
¹⁰ Pediatric Surgery Unit, Buergerhospital and Clementine Kinderhospital, Frankfurt, Germany.
¹¹ Department of Paediatrics Surgery, Muenchen Klinik gGmbH, Munich Clinic Schwabing, Munich, Germany.
¹² Department of Pediatric Surgery, General Hospital, Chemnitz, Germany.
¹³ Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany.
¹⁴ Department of Pediatric and Adolescent Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany.
¹⁵ Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany.
¹⁶ Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
¹⁷ Division of Neonatology and Pediatric Intensive Care Medicine, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

PMID: 35362267
DOI: 10.1002/bdr2.2008

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

Corina E Thiem et al. Birth Defects Res. 2022 Jun.

. 2022 Jun;114(10):478-486.

doi: 10.1002/bdr2.2008. Epub 2022 Mar 31.

Authors

Affiliations

¹ Institute of Human Genetics, Medical Faculty of the University Bonn & University Hospital Bonn, Bonn, Germany.
² Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany.
³ Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
⁴ Research Center On Rare Kidney Diseases (RECORD), University Hospital Erlangen, Erlangen, Germany.
⁵ Department of General, Visceral, Vascular and Thoracic Surgery, Unit of Pediatric Surgery, University Hospital Bonn, Bonn, Germany.
⁶ Clinic for Paediatric Surgery and Paediatric Urology, Klinikum Bremen-Mitte, Bremen, Germany.
⁷ Department of Pediatric Surgery and Urology, Cnopf'sche Kinderklinik, Nürnberg, Germany.
⁸ Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany.
⁹ Department of Pediatric Surgery, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
¹⁰ Pediatric Surgery Unit, Buergerhospital and Clementine Kinderhospital, Frankfurt, Germany.
¹¹ Department of Paediatrics Surgery, Muenchen Klinik gGmbH, Munich Clinic Schwabing, Munich, Germany.
¹² Department of Pediatric Surgery, General Hospital, Chemnitz, Germany.
¹³ Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany.
¹⁴ Department of Pediatric and Adolescent Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany.
¹⁵ Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany.
¹⁶ Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
¹⁷ Division of Neonatology and Pediatric Intensive Care Medicine, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

PMID: 35362267
DOI: 10.1002/bdr2.2008

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.

Keywords: anorectal malformation; birth defects; candidate gene; penetrance; variants.

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

Affiliations

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

Authors

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Abstract

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