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

Hosneara Akter,Mazharul Islam,K M Furkan Uddin,Darren D O’Rielly,Mohammad Shahnoor Hossain,Mohammed Nazmul Ahsan,Tahrima Arman Tusty,Ghausia Begum,Bakhrom K Berdeiv,Reem Abdel Hameid,Md Atikur Rahaman,Mohammad Shaiful Islam ,Sharmin Jahan,Nasna Nassir,Shaoli Sarkar,A.h.m Nurun Nabi ,Nushrat Jahan Dity,Mohammad Basiruzzaman,Elaine T Lim,Marc Woodbury‐Smith ,Dimitri J Stavropoulos ,Stephen W Scherer,Mohammed Uddin

doi:10.1038/s41525-021-00173-0

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.

Highlights

Rare genetic disorders, while individually uncommon, collectively impact significant numbers worldwide[1], with approximately 7,000 rare diseases estimated to affect an estimated 350 million people (European Organization for Rare Diseases; EURORDIS)
We report seven (7) extremely rare recessive variants that are potentially causal in a range of rare genetic diseases 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)from a small cohort of five unrelated Bangladeshi patients
Our findings demonstrate the potential utility of wholeexome sequencing (WES) as a firstskills, lactic acidosis, and bilateral cerebral and cerebellum line diagnostic approach in patients lacking a clear differential leukodystrophy (Table 1)

Summary

INTRODUCTION

While individually uncommon, collectively impact significant numbers worldwide[1], with approximately 7,000 rare diseases estimated to affect an estimated 350 million people (European Organization for Rare Diseases; EURORDIS). These disorders encompass a spectrum of rare complex clinical manifestations[2,3] that can be difficult to diagnose and pinpoint causation. We performed WES to investigate a series of patients from Bangladesh with rare genetic diseases referred for clinical assessment. There is no standard of care for rare disorders in Bangladesh Clinical presentation in these patients was complex[10], prompting referral for genetic diagnosis. We report seven (7) extremely rare recessive variants that are potentially causal in a range of rare genetic diseases 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)from a small cohort of five unrelated Bangladeshi patients

RESULTS

DISCUSSION

METHODS