A case report of an Egyptian family with familial hypercholesterolemia and an exonic LINE-1 insertion in LDLR.

BACKGROUND: Familial hypercholesterolemia (MIM: PS143890) is a genetic disorder characterized by an increase in blood cholesterol. LDLR is one of the genes which their defect contributes to the disorder. Affected individuals may carry a heterozygous variant or homozygous/compound heterozygous variants and those with biallelic pathogenic variants present more severe symptoms. METHOD: We report an Egyptian family with familial hypercholesterolemia. Both the proband and parents have the disorder while a sibling is unaffected. Exome sequencing was performed to identify the causal variant. RESULTS: LINE-1 insertion in exon 7 of LDLR was identified. Both parents have a heterozygous variant while the proband has a homozygous variant. The unaffected sibling did not carry the variant. DISCUSSION: This insertion may contribute to the high prevalence of hypercholesterolemia in Egypt and the finding underscores the importance of implementing mobile element insertion caller in routine bioinformatics pipeline.

The malnutrition screening tool STRONGKIDS performed better than other screening tools for children hospitalised in Egypt.

AIM: To compare the accuracy of three different screening tools, namely, the Paediatric Yorkhill Malnutrition Score (PYMS), Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP), and Screening Tool for Risk on Nutritional Status and Growth (STRONGKIDS), in assessing malnutrition risk in hospitalised children. METHODS: A cross-sectional study was conducted on 300 children aged 6 months to 15 years at Alexandria University Children's Hospital, Egypt. The sensitivity and specificity of each tool were calculated to detect acute and chronic malnutrition, and an agreement test was conducted between the nutritional screening tools. The patients were classified into different nutritional risk groups, and their classification was compared with anthropometric measures and clinical variables, such as the length of hospital stay (LOS). RESULTS: The prevalence of stunting and wasting on admission was found to be 3% and 6.6%, respectively. Children categorised as high-risk on admission had a longer LOS than those at low risk. The agreement test between the STAMP score and STRONGKIDS score on admission showed the most significant agreement, and STRONGKIDS had the best accuracy in detecting acute and chronic malnutrition. CONCLUSION: The comparison of the three screening tools revealed that STRONGKIDS exhibited the best accuracy in detecting acute and chronic malnutrition.

Cyclin D2 gene variance and expression level in pediatric acute lymphoblastic leukemia.

BACKGROUND: Cyclin D2 (CCND2) is a crucial player in cell cycle regulation. CCND2 polymorphisms contribute to cancer predisposition. OBJECTIVES: To evaluate the association of CCND2 rs3217927 single nucleotide polymorphisms (SNP) and its expression levels with acute lymphoblastic leukemia (ALL) susceptibility in Egyptian children and its potential prognostic role. METHODS: The 5' nuclease allelic discrimination assay was used to evaluate the frequency of CCND2 rs3217927 SNP in 80 newly diagnosed children with ALL and 80 age- and sex-matched controls. CCND2 relative expression levels were determined by real-time quantitative polymerase chain reaction. RESULTS: The genotype analysis revealed that the GG genotype and G allele were significantly more prevalent among ALL patients than controls (p Ë‚ .001). Regression analysis demonstrated that Egyptian children carrying only one G allele had about 31-fold increased risk to develop ALL compared to A allele carriers. CCND2 was overexpressed in ALL patients compared to controls (p < .001). The CCND2 overexpression was associated with the GG genotype and G allele (p < .001). Furthermore, G allele was an independent negative prognostic marker for central nervous system (CNS) involvement (odds ratio [OR] = 4.676; 95% confidence interval [CI]: 1.2-18.6), risk stratification (OR = 38; 95% CI: 7.7-188.2), and chemoresistance (OR = 9.864; 95% CI: 5.6-70.3) in ALL patients. CONCLUSIONS: G allele of CCND2 rs3217927 SNP might be associated with increased risk for ALL in Egyptian children besides being an independent negative prognostic marker for their risk stratification and therapeutic outcome. CCND2 rs3217927 SNP genotyping might be used to demarcate ALL patients with aggressive disease phenotypes who may be candidate for alternative targeted therapeutic strategies.

Clinically Relevant KCNQ1 Variants Causing KCNQ1-KCNE2 Gain-of-Function Affect the Ca2+ Sensitivity of the Channel.

Dominant KCNQ1 variants are well-known for underlying cardiac arrhythmia syndromes. The two heterozygous KCNQ1 missense variants, R116L and P369L, cause an allelic disorder characterized by pituitary hormone deficiency and maternally inherited gingival fibromatosis. Increased K+ conductance upon co-expression of KCNQ1 mutant channels with the beta subunit KCNE2 is suggested to underlie the phenotype; however, the reason for KCNQ1-KCNE2 (Q1E2) channel gain-of-function is unknown. We aimed to discover the genetic defect in a single individual and three family members with gingival overgrowth and identified the KCNQ1 variants P369L and V185M, respectively. Patch-clamp experiments demonstrated increased constitutive K+ conductance of V185M-Q1E2 channels, confirming the pathogenicity of the novel variant. To gain insight into the pathomechanism, we examined all three disease-causing KCNQ1 mutants. Manipulation of the intracellular Ca2+ concentration prior to and during whole-cell recordings identified an impaired Ca2+ sensitivity of the mutant KCNQ1 channels. With low Ca2+, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component. These features were absent in mutant KCNQ1 channels and in wild-type channels co-expressed with calmodulin and exposed to high intracellular Ca2+. Moreover, co-expression of calmodulin with wild-type Q1E2 channels and loading the cells with high Ca2+ drastically increased Q1E2 current amplitudes, suggesting that KCNE2 normally limits the resting Q1E2 conductance by an increased demand for calcified calmodulin to achieve effective channel opening. Our data link impaired Ca2+ sensitivity of the KCNQ1 mutants R116L, V185M and P369L to Q1E2 gain-of-function that is associated with a particular KCNQ1 channelopathy.