Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Mary R Sy¹, Jaynee Chauhan², Katrina Prescott², Aliza Imam², Alison Kraus², Ana Beleza³, Lee Salkeld⁴, Saraswati Hosdurga⁵, Michael Parker⁶, Pradeep Vasudevan⁷, Lily Islam⁸, Himanshu Goel^{9

10}, Nicole Bain¹¹, Soo-Mi Park¹², Shehla Mohammed¹³, Klaus Dieterich^{14

15}, Charles Coutton^{14

16}, Véronique Satre^{14

16}, Gaëlle Vieville¹⁴, Alan Donaldson¹⁷, Claire Beneteau¹⁸, Jamal Ghoumid¹⁹, Kris Van Den Bogaert²⁰, Anneleen Boogaerts²⁰, Elise Boudry²¹, Clémence Vanlerberghe¹⁹, Florence Petit¹⁹, Laura Bernardini²², Barbara Torres²², Teresa Mattina^{23

24}, Diana Carli²⁵, Giorgia Mandrile²⁶, Michele Pinelli^{27

28}, Nicola Brunetti-Pierri^{28

29}, Katherine Neas³⁰, Rachel Beddow³¹, Pernille M Tørring³², Flavio Faletra³³, Beatrice Spedicati³⁴, Paolo Gasparini^{33

34}, Alessandro Mussa^{25

35}, Giovanni Battista Ferrero³⁶, Anne Lampe³⁷, Wayne Lam³⁸, Weimin Bi^{1

39}, Carlos A Bacino¹, Akela Kuwahara^{40

41

42}, Jeffrey O Bush^{40

41

42}, Xiaonan Zhao^{1

39}, Pamela N Luna¹, Chad A Shaw¹, Jill A Rosenfeld¹, Daryl A Scott^{1

43}

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
² Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds, UK.
³ Clinical Genetics Department, University Hospitals Bristol and Weston, Bristol NHS Foundation, Bristol, UK.
⁴ Whiteladies Medical Group, Bristol, UK.
⁵ Community Children's Health Partnership, Sirona Health and Care, Bristol, UK.
⁶ Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁷ University Hospitals of Leicester NHS Trust, Leicester, UK.
⁸ Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
⁹ Hunter Genetics, Hunter New England Local Health District, Waratah, New South Wales, Australia.
¹⁰ University of Newcastle, Callaghan, New South Wales, Australia.
¹¹ Department of Molecular Medicine, New South Wales Health Pathology, Newcastle, New South Wales, Australia.
¹² East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹³ Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹⁴ Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble, Grenoble, France.
¹⁵ INSERM U1216 Grenoble Institut des Neurosciences, Cellular Myology and Pathology, Grenoble, France.
¹⁶ Genetic Epigenetic and Therapies of Infertility Team, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
¹⁷ Clinical Genetics Department, St Michaels Hospital, Bristol, UK.
¹⁸ Nantes Université, CHU de Nantes, UF 9321 de Fœtopathologie et Génétique, Nantes, France.
¹⁹ Université de Lille, ULR7364 RADEME, CHU Lille, Clinique de Génétique Guy Fontaine, Lille, France.
²⁰ Center for Human Genetics, University Hospitals Leuven-KU Leuven, Leuven, Belgium.
²¹ CHU Lille, Institut de Génétique Médicale, Lille, France.
²² Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
²³ Department of Biomedical and Biotechnological Sciences, Medical Genetics, University of Catania, Catania, Italy.
²⁴ Scientific Foundation and Clinic G. B. Morgagni, Catania, Italy.
²⁵ Department of Public Health and Pediatrics, University of Torino, Torino, Italy.
²⁶ Medical Genetics Unit, San Luigi University Hospital, University of Torino, Orbassano, Italy.
²⁷ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
²⁸ Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
²⁹ Department of Translational Medicine, University of Naples Federico II, Naples, Italy.
³⁰ Genetic Health Service NZ, Wellington, New Zealand.
³¹ Wellington Regional Genetics Laboratory, Wellington, New Zealand.
³² Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
³³ Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy.
³⁴ Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
³⁵ Pediatric Clinical Genetics Unit, Regina Margherita Children's Hospital, Torino, Italy.
³⁶ Department of Clinical and Biological Sciences, Università degli Studi di Torino, Torino, Italy.
³⁷ South East Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK.
³⁸ Department of Clinical Genetics, Western General Hospital, Edinburgh, UK.
³⁹ Baylor Genetics, Houston, Texas, USA.
⁴⁰ Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, California, USA.
⁴¹ Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
⁴² Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA.
⁴³ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.

PMID: 36135330
PMCID: PMC9669235
DOI: 10.1002/ajmg.a.62976

Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Mary R Sy et al. Am J Med Genet A. 2022 Dec.

. 2022 Dec;188(12):3492-3504.

doi: 10.1002/ajmg.a.62976. Epub 2022 Sep 22.

Authors

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
² Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds, UK.
³ Clinical Genetics Department, University Hospitals Bristol and Weston, Bristol NHS Foundation, Bristol, UK.
⁴ Whiteladies Medical Group, Bristol, UK.
⁵ Community Children's Health Partnership, Sirona Health and Care, Bristol, UK.
⁶ Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁷ University Hospitals of Leicester NHS Trust, Leicester, UK.
⁸ Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
⁹ Hunter Genetics, Hunter New England Local Health District, Waratah, New South Wales, Australia.
¹⁰ University of Newcastle, Callaghan, New South Wales, Australia.
¹¹ Department of Molecular Medicine, New South Wales Health Pathology, Newcastle, New South Wales, Australia.
¹² East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹³ Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹⁴ Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble, Grenoble, France.
¹⁵ INSERM U1216 Grenoble Institut des Neurosciences, Cellular Myology and Pathology, Grenoble, France.
¹⁶ Genetic Epigenetic and Therapies of Infertility Team, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
¹⁷ Clinical Genetics Department, St Michaels Hospital, Bristol, UK.
¹⁸ Nantes Université, CHU de Nantes, UF 9321 de Fœtopathologie et Génétique, Nantes, France.
¹⁹ Université de Lille, ULR7364 RADEME, CHU Lille, Clinique de Génétique Guy Fontaine, Lille, France.
²⁰ Center for Human Genetics, University Hospitals Leuven-KU Leuven, Leuven, Belgium.
²¹ CHU Lille, Institut de Génétique Médicale, Lille, France.
²² Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
²³ Department of Biomedical and Biotechnological Sciences, Medical Genetics, University of Catania, Catania, Italy.
²⁴ Scientific Foundation and Clinic G. B. Morgagni, Catania, Italy.
²⁵ Department of Public Health and Pediatrics, University of Torino, Torino, Italy.
²⁶ Medical Genetics Unit, San Luigi University Hospital, University of Torino, Orbassano, Italy.
²⁷ Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
²⁸ Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
²⁹ Department of Translational Medicine, University of Naples Federico II, Naples, Italy.
³⁰ Genetic Health Service NZ, Wellington, New Zealand.
³¹ Wellington Regional Genetics Laboratory, Wellington, New Zealand.
³² Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
³³ Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy.
³⁴ Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
³⁵ Pediatric Clinical Genetics Unit, Regina Margherita Children's Hospital, Torino, Italy.
³⁶ Department of Clinical and Biological Sciences, Università degli Studi di Torino, Torino, Italy.
³⁷ South East Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK.
³⁸ Department of Clinical Genetics, Western General Hospital, Edinburgh, UK.
³⁹ Baylor Genetics, Houston, Texas, USA.
⁴⁰ Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, California, USA.
⁴¹ Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
⁴² Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA.
⁴³ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.

PMID: 36135330
PMCID: PMC9669235
DOI: 10.1002/ajmg.a.62976

Abstract

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.

Keywords: Fanconi anemia; NRXN1; TCF4; esophageal atresia; exome sequencing; tracheoesophageal fistula.

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Conflict of interest statement

CONFLICT OF INTEREST: Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), which performs genetic testing and derives revenue. The Department of Molecular & Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at BG.

Figures

**Figure 1.. Generation and evaluation of EA/TEF-specific pathogenicity scores.**
A) Receiver operating characteristic (ROC) style curves were generated in validation studies of our machine learning scoring approach using individual knowledge sources (colored) and the average score from all knowledge sources (black). The positive area underneath each curve indicates that our scoring approach identified training set genes known to cause EA/TEF more efficiently than random chance (diagonal dashed line). B) After validation, EA/TEF-specific pathogenicity scores were calculated for all RefSeq genes. The EA/TEF training gene set had a range of 72.6%−99.9% with median score of 99% with *CPLANE2* (72.6%), *TCOF1* (74.2%), *EFTUD2* (80.2%), *SNRPN* (83.8%) and *VANGL1* (84.6%) being outliers. This is significantly higher than the 50% median score (dashed line) for all RefSeq genes. Epi = Epigenetic histone modifications data from NIH Roadmap Epigenomics Mapping Consortium, Exp = the GeneAtlas expression distribution, GO = Gene Ontology, MGI = the Mouse Genome Database, PINA = the Protein Interaction Network Analysis platform, TF = transcription factor binding data from NIH Roadmap Epigenomics Mapping Consortium.

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Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Affiliations

Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Authors

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Abstract

Conflict of interest statement

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