Unraveling the Genetic Basis of Congenital Limb Anomalies in Eight Families.

Limb abnormalities are the second most frequent birth defects seen in infants, after congenital heart disease. Over the past 150 years, more than 50 classifications for limb malformations based on morphology and osseous anatomy have been presented. The goal of the current study is to investigate the genetic basis of congenital limb abnormalities in the Pakistani population.

Delineating the Disease Boundaries: Homozygous Variants Underlying Nonsyndromic Hearing Loss and Hearing Impairment Infertile Male Syndrome.

Background: Hereditary hearing loss is a genetically heterogeneous neurosensory disorder that affects many people. Deafness and infertility can coexist in some cases, creating the hearing impairment infertile male syndrome. There are several known molecular mechanisms that can cause deafness either on its own or in conjunction with infertility.

Novel pathogenic variants in HR underlie atrichia with papular lesions in a cohort of 10 families.

Atrichia with papular lesions (APL) is a hair abnormality characterized by loss of hair on the scalp and rest of the body. In a few cases, hair loss is accompanied by the appearance of keratotic papules on the body. It is inherited in an autosomal recessive manner.

A novel homozygous FAM92A gene (CIBAR1) variant further confirms its association with non-syndromic postaxial polydactyly type A9 (PAPA9).

Polydactyly is a very common digit anomaly, having extra digits in hands and/or toes. Non-syndromic polydactyly in both autosomal dominant and autosomal recessive forms are caused by disease-causing variants in several genes, including GLI1, GLI3, ZNF141, FAM92A, IQCE, KIAA0825, MIPOL1, STKLD1, PITX1, and DACH1. Whole exome sequencing (WES) followed by bi-directional Sanger sequencing was performed for the single affected individual (II-1) of the family to reveal the disease causative variant/gene.

Clinical and genetic investigation of 14 families with various forms of short stature syndromes.

Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology.

Loss-of-function variant in the LRR domain of SLITRK2 implicated in a neurodevelopmental disorder.

Neurodevelopmental disorders are characterized by different combinations of intellectual disability (ID), communication and social skills deficits, and delays in achieving motor or language milestones. SLITRK2 is a postsynaptic cell-adhesion molecule that promotes neurite outgrowth and excitatory synapse development. In the present study, we investigated a single patient segregating Neurodevelopmental disorder.

A variant in the LDL receptor-related protein encoding gene LRP4 underlying polydactyly and phalangeal synostosis in a family of Pakistani origin.

A family of Pakistani origin, segregating polydactyly, and phalangeal synostosis in an autosomal dominant manner, has been investigated and presented in the present report. Whole-exome sequencing (WES), followed by segregation analysis using Sanger sequencing, revealed a heterozygous missense variant [c.G1696A, p.

A novel variant in AFF3 underlying isolated syndactyly.

Isolated syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover a novel heterozygous missense variant c.2915G > C: p.

A novel homozygous variant in the GLI1 underlies postaxial polydactyly in a large consanguineous family with intra familial variable phenotypes.

Polydactyly is a human inherited disorder caused by to anomalies in the genes involved in autopod development. The disorder segregates in both autosomal recessive and autosomal dominant form. Up till now, eleven genes causing non-syndromic polydactyly, have been identified.

A splice site variant in TCTN3 underlies an atypical form of orofaciodigital syndrome IV.

Orofaciodigital syndrome (OFD) is clinically heterogeneous and is characterized by abnormalities in the oral cavity, facial features, digits, and central nervous system. At least 18 subtypes of the condition have been described in the literature. OFD is caused by variants in several genes with overlapping phenotypes.

Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome.

Cenani-Lenz syndrome (CLS) is a rare autosomal-recessive congenital disorder affecting development of distal limbs. It is characterized mainly by syndactyly and/or oligodactyly, renal anomalies, and characteristic facial features. Mutations in the LRP4 gene, located on human chromosome 11p11.

Loss of Function Variants in the XPC Causes Severe Xeroderma Pigmentosum in Three Large Consanguineous Families.

Background: Xeroderma pigmentosum (XP) is a rare recessively inherited disorder that presents clinical and genetic heterogeneity. Mutations in eight genes, of which seven are involved in nucleotide excision repair (NER) pathway have been reported to cause the XP.

Methods And Results: Three large consanguineous families of Pakistani origin displaying typical clinical hallmarks of XP were evaluated at clinical and molecular level.

Greig Cephalopolysyndactyly Syndrome: Phenotypic Variability Associated with Variants in Two Different Domains of GLI3.

Background: GLI3 is a transcriptional regulator of several genes involved in mammalian skeletal development. Mutations in the pleiotropic gene GLI3 may result in different inherited disorders including Greig cephalopolysyndactyly syndrome (GCPS). GCPS is characterized by mild to severe craniofacial and limb malformations.