A child with dilated cardiomyopathy and homozygous splice site variant in FLNC gene.

FLNC gene encodes for Filamin-C (FLNC) protein, a sacromeric protein with important structural and signaling functions in the myocyte. Pathogenic dominant variants in FLNC were initially linked to myofibrillar myopathy and over time, evidence showed association of this gene with different forms of autosomal dominant cardiomyopathy including hypertrophic, dilated and restrictive forms. Recently, two cases of recessive FLNC mutations have been reported by Reinstein et al. and Kölbel et al., one with only cardiomyopathy and other with only myopathy. In this report, we describe a third case, a boy who was diagnosed at 10 years of age with shortness of breath and dilated cardiomyopathy who on sequencing was found to have a novel homozygous splice site variant (NM_001458.4 c.2122-1G>C) in FLNC. This case suggests that the phenotype associated with variants in FLNC is very heterogenous and can be inherited in dominant or recessive forms, with later being more severe and of earlier onset.

Phenotype and genotype of 15 Saudi patients with achromatopsia: A case series.

PURPOSE: Achromatopsia is a rare stationary retinal disorder that primarily affects the cone photoreceptors. Individuals with achromatopsia present with photophobia, nystagmus, reduced visual acuity (VA), and color blindness. Multiple genes responsible for achromatopsia have been identified (e.g. cyclic nucleotide-gated channel subunit alpha 3 [CNGA3] and activating transcription factor 6). Studies have assessed the role of gene therapy in achromatopsia. Therefore, for treatment and prevention, the identification of phenotypes and genotypes is crucial. Here, we described the clinical manifestations and genetic mutations associated with achromatopsia in patients from Saudi Arabia. METHODS: This case series study included 15 patients with clinical presentations, suggestive of achromatopsia, who underwent ophthalmological and systemic evaluations. Patients with typical achromatopsia phenotype underwent genetic evaluation using whole-exome testing. RESULTS: All patients had nystagmus (n = 15) and 93.3% had photophobia (n = 14). In addition, all patients (n = 15) had poor VA. Hyperopia with astigmatism was observed in 93.3% (n = 14) and complete color blindness in 93.3% of the patients (n = 14). In the context of family history, both parents of all patients (n = 15) were genetic carriers, with a high consanguinity rate (82%, n = 9 families). Electroretinography showed cone dysfunction with normal rods in 66.7% (n = 10) and both cone-rod dysfunction in 33.3% (n = 5) patients. Regarding the genotypic features, 93% of patients had variants in CNGA3 (n = 14) categorized as pathogenic Class 1 (86.7%, n = 13). Further, 66.7% (n = 10) of patients also harbored the c.661C>T DNA variant. Further, the patients were homozygous for these mutations. Three other variants were also identified: c.1768G>A (13.3%, n = 2), c.830G>A (6.6%, n = 1), and c. 822G >T (6.6%, n = 1). CONCLUSION: Consanguinity and belonging to the same tribe are major risk factors for disease inheritance. The most common genotype was CNGA3 with the c.661C>T DNA variant. We recommend raising awareness among families and providing genetic counseling for this highly debilitating disease.

Case report: A founder UGDH variant associated with developmental epileptic encephalopathy in Saudi Arabia.

Congenital disorders of glycosylation (CDG) are a group of more than 100 rare genetic disorders characterized by impaired glycosylation of proteins and lipids. The clinical presentation of CDG varies tremendously, from single-organ to multi-organ involvement and from prenatal death to a normal adult phenotype. In this case study, we report a large consanguineous family with multiple children suffering from cerebral palsy, seizure, developmental and epileptic encephalopathy, and global developmental delay. Whole-exome sequencing (WES) analysis revealed a homozygous variant in the UDP-glucose dehydrogenase (UGDH) gene (c.950G>A; p.R317Q) which segregates with the familial phenotype with a plausible autosomal recessive mode of inheritance, indicating a potential disease-causing association. The UGDH gene encodes the UDP-glucose dehydrogenase, a key enzyme in the synthesis of specific extracellular matrix constituents (proteoglycans and glycolipids) involved in neural migration and connectivity during early brain development. Many pathogenic mutations of UGDH have been reported in recent literature works. However, the variant identified in this study has been observed only in the Saudi population (13 families) and not in any other ethnic background, suggesting that it may be an ancient founder mutation.

Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish.

Von Willebrand A domain-containing protein 8 (VWA8), also named KIAA0564, is a poorly characterized, mitochondrial matrix-targeted protein having a putative ATPase activity. VWA8 is comprising of ATPase-associated domains and a VWFA domain associated with ATPase activity inside the cell. In the present study, we describe a large consanguineous family of Saudi origin segregating a complex developmental syndrome in an autosomal recessive fashion. All the affected individuals exhibited severe developmental disorders. DNA from three patients was subjected to whole-exome sequencing followed by Sanger sequencing. VWA8 knock-down zebrafish morpholinos were used to study the phenotypic effect of this gene on zebrafish development. A homozygous missense variant [c.947A > G; p.(Asp316Gly)] was identified in exon 8 of the VWA8 gene, which perfectly segregated with the disease phenotype. Using zebrafish morpholino, we observed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism. This is the first homozygous variant identified in the VWA8 gene underlying global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations in humans. We provide genetic and molecular evidence using zebrafish morpholino for a homozygous variant in the VWA8 gene, associated with such a complex developmental syndrome in humans.

Serum Sickness following Tetanus Toxoid Injection.

Serum sickness is an allergic reaction that frequently occurs in patients after the injection of foreign protein or serum. It is characterized by fever, skin rash, enlarged lymph nodes, and painful joints. In this case, we describe a case of 6-year-old girl who developed a rash and arthralgia after being vaccinated with tetanus toxoid injection after a cut wound.

A systematic comparison between infant formula compositions using the Bray-Curtis Similarity Index.

BACKGROUND: Making an informed choice between the available infant formulas is challenging, as there is no unbiased tool allowing a systematic comparison between the very long lists of infant formula compositions. AIM: The aim is to present the Bray-Curtis Similarity Index (BCSI) as a tool for systematic comparison between standard stage-1 infant formula (SS-1-IF) compositions. METHODS: We obtained the nutrient levels from the packaging labels of 23 SS-1-IFs available in Al-Ahsa, Saudi Arabia, in April 2018. The international legislations that launched infant formula standards endorse targeting the minimum rather than the maximum proposed nutrients levels. Thus, we blindly compared between displayed nutrients levels on each of the 23-studied SS-1-IF and the minimum international proposed nutrient levels via using the BCSI. RESULTS: The range of the total displayed components was 38-57. Except for docosahexaenoic acid, all displayed components were within the standard recommended range. The BCSI summarized all displayed nutrients in a single number. The BCSI of the studied SS-1-IF ranged from 0.4141 to 0.79730. We ranked the 23 studied SS-1-IFs based on the higher BCSI is the closer to the minimum proposed nutrient levels. A dendrogram segregated the SS-1-IFs into four clusters based on their BSCI and total numbers of all displayed components. CONCLUSIONS: We think the BCSI is an appropriate tool for a systematic comparison between SS-1-IFs compositions and may help for choosing a SS-1-IF.