Biallelic variants in CHST3 cause Spondyloepiphyseal dysplasia with joint dislocations in three Pakistani kindreds.

BACKGROUND: Skeletal dysplasia is a heterogeneous group of disorders. Spondyloepiphyseal dysplasias comprise one subgroup. Deficiency of carbohydrate sulfotransferase 3 has been reported in a small number of patients with recessively inherited spondyloepiphyseal dysplasia with joint dislocation, short stature and scoliosis. We report here molecular and clinical findings of affected individuals in three consanguineous Pakistani families. Affected individuals in all three families had a uniform phenotype including severe short stature, multiple dislocated joints, progressive scoliosis and facial dysmorphism. METHODS: Clinical evaluation was done for three unrelated families. Radiological survey of bones was completed for patients from two of the families. Whole exome sequencing index patients from each family was performed followed by Sanger sequencing for validation of segregation of identified variants in respective families. In-silico analysis for determining pathogenicity of identified variants and conservation was done. RESULTS: Whole-exome sequencing revealed biallelic variants c.590 T > C;p.(Leu197Pro), c.603C > A;p.(Tyr201Ter) and c.661C > T;p.(Arg221Cys) in CHST3 (NM_004273.5) in the three families with eight, five and two affected individuals, respectively. Contrary to previous reports, affected individuals in none of the families exhibited a hearing loss. CONCLUSION: We describe genotypic and phenotypic findings of three unrelated families with spondyloepiphyseal dysplasia. Our study confirms phenotypic variability and adds to the genotypic spectrum of spondyloepiphyseal dysplasia.

Analysis of pattern of mortality in Medicine and Allied Departments at a tertiary care hospital in Islamabad: A losing battle against sepsis.

OBJECTIVE: To identify the pattern of mortality in medical wards of a tertiary care hospital. METHODS: This retrospective study was conducted at the Khan Research Laboratories Hospital, Islamabad, Pakistan, and comprised medical records of people who died during hospital stay between December 2013 and November 2014.SPSS 11 was used for data analysis. RESULTS: Of the 3,228 admissions, 105(3.25%) patients expired. Of them, 41(39.04%) were men with a mean age of 55±13.48 years (range: 17-88 years) and 64±11.76 (60.9%) were women with a mean age of 61±15.5 years (range: 23-91 years). The mean length of time between admission and death was 6.58±3.7 days (range: 1-33 days). The causes of death were categorised as infectious in 37(35.23%) patients, cancer-related in 20(19.045%), pulmonary in 19(18.09%), cardiovascular in 18(17.14%), gastrointestinal and neurological in 13(12.38%) each, nephrology in 10(9.52%), autoimmune disorders in 6(5.71%) and miscellaneous in 9(8.57%). Complications of sepsis were the most common cause of death in 38(36.19%) cases. CONCLUSIONS: Sepsis, primarily from pneumonia, was the major cause of mortality.

A novel splice-site mutation in ALS2 establishes the diagnosis of juvenile amyotrophic lateral sclerosis in a family with early onset anarthria and generalized dystonias.

The diagnosis of childhood neurological disorders remains challenging given the overlapping clinical presentation across subgroups and heterogeneous presentation within subgroups. To determine the underlying genetic cause of a severe neurological disorder in a large consanguineous Pakistani family presenting with severe scoliosis, anarthria and progressive neuromuscular degeneration, we performed genome-wide homozygosity mapping accompanied by whole-exome sequencing in two affected first cousins and their unaffected parents to find the causative mutation. We identified a novel homozygous splice-site mutation (c.3512+1G>A) in the ALS2 gene (NM_020919.3) encoding alsin that segregated with the disease in this family. Homozygous loss-of-function mutations in ALS2 are known to cause juvenile-onset amyotrophic lateral sclerosis (ALS), one of the many neurological conditions having overlapping symptoms with many neurological phenotypes. RT-PCR validation revealed that the mutation resulted in exon-skipping as well as the use of an alternative donor splice, both of which are predicted to cause loss-of-function of the resulting proteins. By examining 216 known neurological disease genes in our exome sequencing data, we also identified 9 other rare nonsynonymous mutations in these genes, some of which lie in highly conserved regions. Sequencing of a single proband might have led to mis-identification of some of these as the causative variant. Our findings established a firm diagnosis of juvenile ALS in this family, thus demonstrating the use of whole exome sequencing combined with linkage analysis in families as a powerful tool for establishing a quick and precise genetic diagnosis of complex neurological phenotypes.