A Comprehensive review of genetic skeletal disorders reported from Pakistan: A brief commentary

Umair, Muhammad; Ahamd, Farooq; Bilal, Muhammad; Asiri, Abdulaziz; Younus, Muhammad; Khan, Amjad

doi:10.1016/j.mgene.2019.100559

Cited by 19 publications

(17 citation statements)

References 65 publications

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“…Consanguineous marriages have become an alarming issue in a culturally rich and religious country like Pakistan, which increase the likelihood for single gene disorder (autosomal recessive). It has been estimated that almost 82.5% of Pakistani parents are blood relatives (20, 21). In such a situation, next generation sequencing technologies such as WES and whole genome sequencing (WGS) is a preferred choice for quick and efficient molecular diagnostic tool in single gene disorders.…”

Section: Discussionmentioning

confidence: 99%

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Biallelic Missense Mutation in the ECEL1 Underlies Distal Arthrogryposis Type 5 (DA5D)

et al. 2019

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Distal arthrogryposis (DA) is a heterogeneous sub-group of arthrogryposis multiplex congenita (AMC), mostly characterized by having congenital contractures affecting hands, wrists, feet, and ankles. Distal arthrogryposis is mostly autosomal dominantly inherited, while only one sub-type DA type 5D is inherited in an autosomal recessive manner. Clinically, DA5D is described having knee extension contractures, micrognathia, distal joint contractures, clubfoot, ptosis, contractures (shoulders, elbows, and wrists), and scoliosis. Using whole exome sequencing (WES) followed by Sanger sequencing, we report on a first familial case of DA5D from Pakistani population having a novel biallelic missense mutation (c.158C>A, p.Pro53Leu) in the ECEL1 gene. Our result support that homozygous mutations in ECEL1 causes DA5D and expands the clinical and allelic spectrum of ECEL1 related contracture syndromes.

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Section: Discussionmentioning

confidence: 99%

“…ECEL1 encodes the endothelin-converting enzyme-like 1, a membrane-bound metalloproteinase, which is similar in structure to the endothelin-converting enzyme (ECE) (21). It is highly expressed in neurons within the peripheral and central nervous system and belongs to the neprilysin family of zinc metalloendopeptidases (2, 22–25).…”

Section: Discussionmentioning

confidence: 99%

Biallelic Missense Mutation in the ECEL1 Underlies Distal Arthrogryposis Type 5 (DA5D)

et al. 2019

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“…The nonsense variant (c.1098C>A; p.Cys366 * ) results in a Cysteine amino acid substitution to stop codon at a position 366 which results in a shorter protein formation (21). A number of families has been reported previously from Pakistan having different mutations in the WNT10B leading to SHFM phenotypes (22)(23)(24). Khan et al (9), Aziz et al (24), and Ullah et al (25), studied several Pakistani consanguineous SHFM families using linkage analysis followed by direct sequencing and identified pathogenic variants in the WNT10B gene (9,24,25).…”

Section: Discussionmentioning

confidence: 99%

A Novel Homozygous Nonsense Mutation p.Cys366* in the WNT10B Gene Underlying Split-Hand/Split Foot Malformation in a Consanguineous Pakistani Family

et al. 2020

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Split hand/split foot malformation (SHFM) or ectrodactyly is characterized by a deep median cleft of the hand or foot, hypoplasia or aplasia of the metacarpals, metatarsals, and phalanges. It is a clinically and genetically heterogeneous group of limb malformations. This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive SHFM. Peripheral blood samples were obtained, DNA was extracted, WNT10B coding and noncoding regions were PCR amplified and Sanger sequencing was performed using workflow suggested by Thermo Fisher Scientific. A novel homozygous nonsense variant (c.1098C>A; p.Cys366 *) was identified in the WNT10B gene in the index patients, which probably explains SHFM type 6 in this family in comparison with similar data from the literature.

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“…It has been shown that the EVC/EVC2 complex is involved in the transduction of Sonic hedgehog signaling (Louie et al, 2020;. More than 80 EVC gene mutations have been reported in cases of EvC syndrome (Umair et al, 2017;Umair et al, 2019). The majority of the mutations produce premature termination codons, and are, therefore, predicted to lead to nonsense-mediated mRNA decay, or truncated proteins (Huang et al, 2019;Tompson et al, 2006).…”

Section: Sanger Sequencing Confirmed the Segregation Of Evc Variantmentioning

confidence: 99%

An intrafamilial phenotypic variability in Ellis‐Van Creveld syndrome due to a novel 27 bps deletion mutation

Zaka

Shahzad

Rao

et al. 2021

American J of Med Genetics Pt A

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Ellis-van Creveld (EvC) syndrome is an autosomal recessive disease, characterized by ectodermal, skeletal, and cardiac anomalies. We report intrafamilial phenotypic variability in three new EvC syndrome cases. Affected males in this study showed only ectodermal abnormalities, whereas an affected female showed the classical presentation of EvC Syndrome, including bilateral postaxial polydactyly of hands and feet, and congenital heart defects. Whole exome sequencing was performed to identify the causative variant, followed by validation and segregation analysis using Sanger sequencing. A homozygous deletion variant (c.731_757del) was identified in exon 6 of the EVC gene (NM_153717.2). The identified variant is considered to be the most likely candidate variant for the EvC syndrome in the family based on previous reports validating the role of EVC variants in the EvC syndrome. The disease correctly segregated in the family members, as all affected members were homozygous, and obligate carriers were heterozygous. Our family is remarkable in highlighting the variable expressivity of the EvC phenotype within the same family, due to a homozygous deletion mutation in the EVC gene. The variable expressivity might be due to the

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A Comprehensive review of genetic skeletal disorders reported from Pakistan: A brief commentary

Cited by 19 publications

References 65 publications

Biallelic Missense Mutation in the ECEL1 Underlies Distal Arthrogryposis Type 5 (DA5D)

Biallelic Missense Mutation in the ECEL1 Underlies Distal Arthrogryposis Type 5 (DA5D)

A Novel Homozygous Nonsense Mutation p.Cys366* in the WNT10B Gene Underlying Split-Hand/Split Foot Malformation in a Consanguineous Pakistani Family

An intrafamilial phenotypic variability in Ellis‐Van Creveld syndrome due to a novel 27 bps deletion mutation

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