Genome sequencing reveals novel causative structural and single nucleotide variants in Pakistani families with congenital hypogonadotropic hypogonadism
Yassine Zouaghi,
Anbreen Mazhar Choudhary,
Saba Irshad,
Michela Adamo,
Khaleeq ur Rehman,
Ambrin Fatima,
Mariam Shahid,
Nida Najmi,
Fernanda De Azevedo Correa,
Imen Habibi,
Alexia Boizot,
Nicolas J. Niederländer,
Muhammad Ansar,
Federico Santoni,
James Acierno,
Nelly Pitteloud
Affiliations
Yassine Zouaghi
University of Lausanne
Anbreen Mazhar Choudhary
School of Biochemistry and Biotechnology, University of the Punjab
Saba Irshad
School of Biochemistry and Biotechnology, University of the Punjab
Michela Adamo
University of Lausanne
Khaleeq ur Rehman
FMH College of Medicine & Dentistry
Ambrin Fatima
Department of Biological and Biomedical Sciences, Aga Khan University
Mariam Shahid
Centre of Excellence in Molecular Biology, University of the Punjab
Nida Najmi
Department of Obstetrics and Gynaecology, The Aga Khan University Hospital
Fernanda De Azevedo Correa
University of Lausanne
Imen Habibi
University of Lausanne
Alexia Boizot
University of Lausanne
Nicolas J. Niederländer
University of Lausanne
Muhammad Ansar
Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile Des Aveugles
Federico Santoni
University of Lausanne
James Acierno
Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital
Abstract Background/Objectives This study aims to elucidate the genetic causes of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder resulting in GnRH deficiency, in six families from Pakistan. Methods Eighteen DNA samples from six families underwent genome sequencing followed by standard evaluation for pathogenic single nucleotide variants (SNVs) and small indels. All families were subsequently analyzed for pathogenic copy number variants (CNVs) using CoverageMaster. Results Novel pathogenic homozygous SNVs in known CHH genes were identified in four families: two families with variants in GNRHR, and two others harboring KISS1R variants. Subsequent investigation of CNVs in the remaining two families identified novel unique large deletions in ANOS1. Conclusion A combined, systematic analysis of single nucleotide and CNVs helps to improve the diagnostic yield for variants in patients with CHH.
