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

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.

Fig. 1. Pedigree and Sanger validation of all compound heterozygous mutations in two unrelated non-consanguineous families (Patient 2 and 4, respectively).

a, d Pedigree of two non-consanguineous families. Square indicates male and circle indicates female. The filled symbols represent affected individuals and partially filled symbols indicate carrier parents. Open symbols indicate healthy individual. b Chromatograms from Sanger sequencing of heterozygous GNPTAB mutations c.2972dupTand c.3503_3504delTCin father and mother, respectively. c Chromatograms from Sanger sequencing of compound heterozygous GNPTAB mutations c.2972dupT and c.3503_3504delTCin Patient-2. e Chromatograms from Sanger sequencing of heterozygous SURF1 mutations c.792_793delAGand c.229 G > Cin father and mother, respectively. f Chromatograms from Sanger sequencing of compound heterozygous SURF1 mutations c.792_793delAGand c.229 G > Cin patient-4. His elder brother (II:1) was apparently healthy and was not included in this study.

Fig. 2. Sanger validation of all homozygous mutations in DHH, BBS1 and AP4B1 genes.

a, b Forward and reverse strand sequence of novel homozygous missense mutation c.863 G > Cin DHH gene (Patient-1). c, d Forward and reverse strand sequence of homozygous missense mutation c.1339 G > Ain BBS1 gene (Patient-3). e, f Forward and reverse strand sequence of homozygous missense mutation c.1216 C > Tin AP4B1 gene (Patient-5).