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.

Heat-moisture treated waxy highland barley starch: Roles of starch granule-associated surface lipids, temperature and moisture.

Roles of temperature, moisture and starch granule-associated surface lipids (SGASL) during heat-moisture treatment (HMT) of waxy highland barley starch were elucidated. Starch without SGASL showed a higher increase in ratio (1016/993 cm-1) (0.095-0.121), lamellar peak area (88), radius of gyration (Rg1, 0.9-1.8 nm) and power-law exponents (0.19-0.42) than native starch (0.038-0.047, 46, 0.1-0.6 nm, 0.04-0.14), upon the same increase in moisture or temperature. Thus, removing SGASL promoted HMT. However, after HMT (30 % moisture, 120 °C), native starch showed lower relative crystallinity (RC, 11.67 %) and lamellar peak area (165.0), longer lamellar long period (L, 14.99 nm), and higher increase in peak gelatinization temperature (9.2-13.3 °C) than starch without SGASL (12.04 %, 399.2, 14.52 nm, 4.7-6.1 °C). This suggested that the resulting SGASL-amylopectin interaction further destroyed starch structure. Starch with and without SGASL showed similar trends in RC, lamellar peak area, L and Rg1 with increasing temperature, but different trends with increasing moisture, suggesting that removing SGASL led to more responsiveness to the effects of increasing moisture. Removing SGASL resulted in similar trends (RC and lamellar peak area) with increasing moisture and temperature, suggesting that the presence of SGASL induced different effects on moisture and temperature.

Removing starch granule-associated surface lipids affects structure of heat-moisture treated hull-less barley starch.

The effects of starch granule-associated surface lipids removal on hull-less barley starch structure formed by heat-moisture treatment were investigated. Removing surface lipids made the peak at 2θ of 13° disappear and resulted in higher lamellar peak intensity after harsh treatment and a lower reduction in mass fractal dimension (from 2.49 to 2.43) and radius of gyration (from 24.3 to 24.0) when temperature increased from 100 to 120 °C at 20 % moisture. Treatment at 25 % moisture and 120 °C decreased relative crystallinity (from 15.73 % to 7.43 %) and Gaussian peak area (from 646.7 to 137.7) of native starch, and decreased relative crystallinity (from 14.24 % to 12.56 %) and Gaussian peak area (from 604.1 to 539.6) for starch without surface lipids. Different trends of change in lamellar thickness, linear crystallinity, peak temperatures, and enthalpy of gelatinization were observed among modified starches with increasing temperature and/or moisture content. These results demonstrate that removing surface lipids changes structure of heat-moisture treated starch.

Updated strategies for the management, pathogenesis and molecular genetics of different forms of ichthyosis syndromes with prominent hair abnormalities.

Syndromic ichthyosis is rare inherited disorders of cornification with varied disease complications. This disorder appears in seventeen subtypes associated with severe systematic manifestations along with medical, cosmetic and social problems. Syndromic ichthyosis with prominent hair abnormalities covers five major subtypes: Netherton syndrome, trichothiodystrophy, ichthyosis hypotrichosis syndrome, ichthyosis hypotrichosis sclerosing cholangitis and ichthyosis follicularis atrichia photophobia syndrome. These syndromes mostly prevail in high consanguinity states, with distinctive clinical features. The known pathogenic molecules involved in ichthyosis syndromes with prominent hair abnormalities include SPINK5, ERCC2, ERCC3, GTF2H5, MPLKIP, ST14, CLDN1 and MBTPS2. Despite underlying genetic origin, most of the health professionals solely rely on phenotypic expression of these disorders that leads to improper management of patients, hence making these patients living an orphanage life. After dermal features, association of other systems such as nervous system, skeletal system, hair abnormalities or liver problems may sometimes give clues for diagnosis but still leaving place for molecular screening for efficient diagnosis. In this paper, we have presented a review of ichthyosis syndrome with prominent hair abnormalities, with special emphasis on their updated genetic consequences and disease management. Additionally, we aim to update health professionals about the practice of molecular screening in ichthyosis syndromes for appropriate diagnosis and treatment.

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.