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

doi:10.1186/s12864-024-10598-3

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

Department of Biological & Biomedical Sciences, Medical College, Pakistan

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	787
Journal	BMC Genomics
Volume	25
Issue number	1
DOIs	https://doi.org/10.1186/s12864-024-10598-3
Publication status	Published - Dec 2024

Keywords

Congenital hypogonadotropic hypogonadism
Copy number variants
Infertility
Rare endocrine disease
Whole genome sequencing

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10.1186/s12864-024-10598-3

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Zouaghi, Y., Choudhary, A. M., Irshad, S., Adamo, M., Rehman, K. U., Fatima, A., Shahid, M., Najmi, N., De Azevedo Correa, F., Habibi, I., Boizot, A., Niederländer, N. J., Ansar, M., Santoni, F., Acierno, J., & Pitteloud, N. (2024). Genome sequencing reveals novel causative structural and single nucleotide variants in Pakistani families with congenital hypogonadotropic hypogonadism. BMC Genomics, 25(1), Article 787. https://doi.org/10.1186/s12864-024-10598-3

@article{06fbd13adf7a4694884aa34312bd7bff,

title = "Genome sequencing reveals novel causative structural and single nucleotide variants in Pakistani families with congenital hypogonadotropic hypogonadism",

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.",

keywords = "Congenital hypogonadotropic hypogonadism, Copy number variants, Infertility, Rare endocrine disease, Whole genome sequencing",

author = "Yassine Zouaghi and Choudhary, {Anbreen Mazhar} and Saba Irshad and Michela Adamo and Rehman, {Khaleeq ur} and Ambrin Fatima and Mariam Shahid and Nida Najmi and {De Azevedo Correa}, Fernanda and Imen Habibi and Alexia Boizot and Niederl{\"a}nder, {Nicolas J.} and Muhammad Ansar and Federico Santoni and James Acierno and Nelly Pitteloud",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1186/s12864-024-10598-3",

language = "English",

volume = "25",

journal = "BMC Genomics",

issn = "1471-2164",

publisher = "BioMed Central Ltd.",

number = "1",

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Zouaghi, Y, Choudhary, AM, Irshad, S, Adamo, M, Rehman, KU, Fatima, A, Shahid, M, Najmi, N, De Azevedo Correa, F, Habibi, I, Boizot, A, Niederländer, NJ, Ansar, M, Santoni, F, Acierno, J & Pitteloud, N 2024, 'Genome sequencing reveals novel causative structural and single nucleotide variants in Pakistani families with congenital hypogonadotropic hypogonadism', BMC Genomics, vol. 25, no. 1, 787. https://doi.org/10.1186/s12864-024-10598-3

TY - JOUR

T1 - Genome sequencing reveals novel causative structural and single nucleotide variants in Pakistani families with congenital hypogonadotropic hypogonadism

AU - Zouaghi, Yassine

AU - Choudhary, Anbreen Mazhar

AU - Irshad, Saba

AU - Adamo, Michela

AU - Rehman, Khaleeq ur

AU - Fatima, Ambrin

AU - Shahid, Mariam

AU - Najmi, Nida

AU - De Azevedo Correa, Fernanda

AU - Habibi, Imen

AU - Boizot, Alexia

AU - Niederländer, Nicolas J.

AU - Ansar, Muhammad

AU - Santoni, Federico

AU - Acierno, James

AU - Pitteloud, Nelly

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

KW - Congenital hypogonadotropic hypogonadism

KW - Copy number variants

KW - Infertility

KW - Rare endocrine disease

KW - Whole genome sequencing

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U2 - 10.1186/s12864-024-10598-3

DO - 10.1186/s12864-024-10598-3

M3 - Article

C2 - 39143522

AN - SCOPUS:85201285211

SN - 1471-2164

VL - 25

JO - BMC Genomics

JF - BMC Genomics

IS - 1

M1 - 787

ER -

Genome sequencing reveals novel causative structural and single nucleotide variants in Pakistani families with congenital hypogonadotropic hypogonadism

Abstract

Keywords

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