Whole Exome Sequencing Confirms Molecular Diagnostics of Three Pakhtun Families With Autosomal Recessive Epidermolysis Bullosa

Abstract

Epidermolysis bullosa (EB) is a genetic skin disorder that shows heterogeneous clinical fragility. The patients develop skin blisters congenitally or in the early years of life at the dermo-epithelial junctions, including erosions, hyperkeratosis over the palms and soles. The other associated features are hypotrichosis on the scalp, absent or dystrophic nails, and dental anomalies. Molecular diagnosis through whole-exome sequencing (WES) has become one of the successful tool in clinical setups. In this study, three Pakhtun families from the Khyber Pakhtunkhwa province of Pakistan were ascertained. WES analysis of a proband in each family revealed two novel variants (COL17A1: NM_000494.4: c.4041T>G: p.Y1347* and PLEC: NM_201380.3: c.1283_1285delGCT: p.L426del) and one previously known COL17A1: NM_000494.4:c.3067C>T: p.Q1023*) variant in homozygous forms. Sanger sequencing of the identified variants confirmed that the heterozygous genotypes of the obligate carriers. The identified variants have not only increased the mutation spectrum of the COL17A1 and PLEC but also confirms their vital role in the morphogenesis of skin and its associated appendages. WES can be used as a first-line diagnostic tool in genetic testing and counselling families from Khyber Pakhtunkhwa, Pakistan.

Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family

“…Furthermore, the clinical signs of developmental arrest or regression were observed in the patients in this study, and West syndrome patients previously reported with GFM1 pathogenic variants have had this feature in common. However, our patients had no recorded history of infantile spasm of West syndrome(Pavone et al, 2020).Similarly, clinical features of Leigh syndrome, including psychomotor retardation, nystagmus, dysphagia, and failure to thrive, were present; however, enlarged ventricles and lesions in the basal ganglia(Gerards et al, 2016) were not observed in the brain MRI of patient IV-1 in this study. Leigh syndrome alone has more than 95 causative genes(Gerards et al, 2016;Rahman & Rahman, 2018) including…”

“…GFM1 is one of the eight nuclear genes responsible for the transcriptional/translational assembly of the mitochondria, and its alterations have been known for multiple complex deficiencies in Leigh syndrome (Gerards et al, 2016). Online Mendelian Inheritance in Man (OMIM; https://www.omim.org/) has listed more than 50 subtypes of combined oxidative phosphorylation deficiency (COXPDs) phenotypes based on the causative genes.…”

“…The captured genomic regions were sequenced using the NovaSeq platform (Illumina, San Diego, CA). The variants calling, annotation, filtering process, and prioritization were performed as previously described (Fozia et al, 2021; Seo et al, 2020). CNV calling was performed using CoNIFER (http://conifer.sourceforge.net/).…”

Genetic diagnosis of a rare COL7A1 variant causing dystrophic epidermolysis bullosa pruriginosa through whole‑exome sequencing

“…Compared to skin microscopy and classical Sanger sequencing, next-generation sequencing-based whole-exome sequencing (WES) is a more accurate and sensitive technique and has shown promise in improving the diagnosis of DEB, particularly in the differential diagnosis from other types of EB and other genetic diseases (9)(10)(11)(12)(13). The existence of cell-free DNA (cfDNA) in human blood was first reported in 1948 (14).…”