Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh

Hosneara Akter; Mohammad Shahnoor Hossain; Nushrat Jahan Dity; Md Atikur Rahaman; K M Furkan Uddin; Nasna Nassir; Ghausia Begum; Reem Abdel Hameid; Muhammad Sougatul Islam; Tahrima Arman Tusty; Mohammad Basiruzzaman; Shaoli Sarkar; Mazharul Islam; Sharmin Jahan; Elaine T Lim; Marc Woodbury-Smith; Dimitri James Stavropoulos; Darren D O'Rielly; Bakhrom K Berdeiv; A H M Nurun Nabi; Mohammed Nazmul Ahsan; Stephen W Scherer; Mohammed Uddin

doi:10.1038/s41525-021-00173-0

Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh

NPJ Genom Med. 2021 Feb 16;6(1):14. doi: 10.1038/s41525-021-00173-0.

Authors

Hosneara Akter^#^{1

2}, Mohammad Shahnoor Hossain^#³, Nushrat Jahan Dity¹, Md Atikur Rahaman¹, K M Furkan Uddin¹, Nasna Nassir⁴, Ghausia Begum⁴, Reem Abdel Hameid⁴, Muhammad Sougatul Islam⁵, Tahrima Arman Tusty³, Mohammad Basiruzzaman^{1

6}, Shaoli Sarkar^{1

6}, Mazharul Islam^{1

6}, Sharmin Jahan⁷, Elaine T Lim⁸, Marc Woodbury-Smith^{9

10}, Dimitri James Stavropoulos¹¹, Darren D O'Rielly¹², Bakhrom K Berdeiv⁴, A H M Nurun Nabi², Mohammed Nazmul Ahsan³, Stephen W Scherer^{9

13}, Mohammed Uddin¹⁴

Affiliations

¹ Genetics and Genomic Medicine Centre, NeuroGen Children's Healthcare, Dhaka, Bangladesh.
² Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
³ Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh.
⁴ College of Medicine, Mohammed Bin Rashid University of Medicine and Health Science, Dubai, UAE.
⁵ BioTED, Dhaka, Bangladesh.
⁶ Department of Child Neurology, NeuroGen Children's Healthcare, Dhaka, Bangladesh.
⁷ Department of Endocrinology & Metabolism, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.
⁸ Department of Genetics, Harvard Medical School, Boston, USA.
⁹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada.
¹⁰ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
¹¹ Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.
¹² Faculty of Medicine, Memorial University, St. John's, NL, Canada.
¹³ McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁴ College of Medicine, Mohammed Bin Rashid University of Medicine and Health Science, Dubai, UAE. mohammed.uddin@mbru.ac.ae.

^# Contributed equally.

Abstract

Collectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet-Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.