VNtyper enables accurate alignment-free genotyping of MUC1 coding VNTR using short-read sequencing data in autosomal dominant tubulointerstitial kidney disease

Hassan Saei; Vincent Morinière; Laurence Heidet; Olivier Gribouval; Said Lebbah; Frederic Tores; Manon Mautret-Godefroy; Bertrand Knebelmann; Stéphane Burtey; Vincent Vuiblet; Corinne Antignac; Patrick Nitschké; Guillaume Dorval

doi:10.1016/j.isci.2023.107171

VNtyper enables accurate alignment-free genotyping of MUC1 coding VNTR using short-read sequencing data in autosomal dominant tubulointerstitial kidney disease

iScience. 2023 Jun 17;26(7):107171. doi: 10.1016/j.isci.2023.107171. eCollection 2023 Jul 21.

Authors

Hassan Saei¹, Vincent Morinière², Laurence Heidet^{1

3}, Olivier Gribouval¹, Said Lebbah⁴, Frederic Tores⁵, Manon Mautret-Godefroy², Bertrand Knebelmann⁶, Stéphane Burtey^{7

8}, Vincent Vuiblet^{9

10

11}, Corinne Antignac^{1

2}, Patrick Nitschké⁵, Guillaume Dorval^{1

2}

Affiliations

¹ Laboratoire des Maladies Rénales Héréditaires, Inserm UMR 1163, Institut Imagine, Université Paris Cité, Paris, France.
² Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, Assistance publique, Hôpitaux de Paris (AP-HP), Paris, France.
³ Service de Néphrologie Pédiatrique, Centre de Référence MARHEA, Hôpital Necker-Enfants Malades, Assistance publique, Hôpitaux de Paris (AP-HP), Paris, France.
⁴ Département de Santé Publique, Unité de Recherche Clinique, Hôpital Pitié-Salpêtrière, Assistance publique, Hôpitaux de Paris (AP-HP), Paris, France.
⁵ Plateforme Bio-informatique, Inserm UMR 1163, Institut Imagine, Université Paris Cité, Paris, France.
⁶ Service de Néphrologie, Centre de Référence MARHEA, Hôpital Necker-Enfants Malades, Assistance publique, Hôpitaux de Paris (AP-HP), Paris, France.
⁷ Inserm, C2VN, INRAE, C2VN, Aix-Marseille Université, Marseille, France.
⁸ Centre de Néphrologie et Transplantation Rénale, AP-HM Hôpital de la Conception, Marseille, France.
⁹ Service de Néphrologie, CHU de Reims, Reims, France.
¹⁰ Service de Pathologie, CHU De Reims, Reims, France.
¹¹ Institut d'Intelligence Artificielle en Santé, Université de Reims Champagne-Ardenne et CHU de Reims, Reims, France.

Abstract

The human genome comprises approximately 3% of tandem repeats with variable length (VNTR), a few of which have been linked to human rare diseases. Autosomal dominant tubulointerstitial kidney disease-MUC1 (ADTKD-MUC1) is caused by specific frameshift variants in the coding VNTR of the MUC1 gene. Calling variants from VNTR using short-read sequencing (SRS) is challenging due to poor read mappability. We developed a computational pipeline, VNtyper, for reliable detection of MUC1 VNTR pathogenic variants and demonstrated its clinical utility in two distinct cohorts: (1) a historical cohort including 108 families with ADTKD and (2) a replication naive cohort comprising 2,910 patients previously tested on a panel of genes involved in monogenic renal diseases. In the historical cohort all cases known to carry pathogenic MUC1 variants were re-identified, and a new 25bp-frameshift insertion in an additional mislaid family was detected. In the replication cohort, we discovered and validated 30 new patients.

Keywords: Genetics; Genomics; Genotyping; Techniques in genetics.