UNASSIGNED: Familial hemophagocytic lymphohistiocytosis (FHLH) is an inherited life-threatening disease. Five types are identified, with the addition of congenital immunodeficiency syndromes in which HLH is a typical manifestation. The literature on this disease is very scarce in the Middle East, with only a few scattered reports.
UNASSIGNED: We report detailed demographic, clinical, and genomic data from 28 patients diagnosed with primary and familial HLH over the last decade in Qatar. An evaluation was performed of allele frequencies of deleterious variants from 12 primary and familial HLH causative genes on the Qatar Genome Programme (QGP) cohort of 14,669 Qatari individuals.
UNASSIGNED: The genetic diagnosis was obtained in 15 patients, and four novel mutations in Perforin 1 (PRF1), UNC13D, LYST, and RAB27A genes were found. We identified 22,945 low/high/moderate/modifier impact variants significantly enriched in the QGP in those 12 genes. The variants rs1271079313 in PRF1 and rs753966933 in RAB27A found in our patient cohort were significantly more prevalent in the QGP compared to the Genome Aggregation Database (gnomAD) database, with a high carrier frequency in the Qatari population.
UNASSIGNED: We established the first primary and familial HLH Registry in the Gulf Region and identified novel possibly pathogenic variants present at higher frequency in the Qatari population, which could be used for screening purposes. Raising awareness about primary and familial HLH and implementing screening activities in the Qatari highly inbred population could stem into more comprehensive premarital and prenatal evaluations and faster diagnosis.

OBJECTIVE: To describe the clinical characteristics of Chinese cystic fibrosis (CF) patients and to investigate the variants of CFTR and their potential pathogenicity.
METHODS: Chinese patients with potential CF diagnosis were studied. Clinical data were reviewed retrospectively from medical records. Whole exome sequencing and genetic evaluation were conducted to explore potential gene variants. The disruption of the variants to protein structure and function was explored and validated using in vitro experiments and in silico analysis.
RESULTS: Four patients were recruited to the study, three of them were diagnosed as CF, and one was diagnosed as CFTR-related disorder. The age at symptom onset for the patients in this study ranged from newborn to 6 years, while the age at diagnosis varied from 3 to 11 years. All four patients exhibited bilateral diffuse bronchiectasis with Pseudomonas aeruginosa infections, and three of them had malnutrition. Finger clubbing was observed in three patients, two of whom displayed mixed ventilatory dysfunction. The CFTR variants spectrum of Chinese children with CF differs from that of Caucasian. A total of six variants were identified, two of which were first reported (c.1219G > T [p.Glu407*] and c.1367delT [p.Ala457Leufs*12]). The nonsense variants c.1219G > T, c.1657C > T and c.2551C > T and the frameshift variant c.1367delT were predicted to introduce premature stop codon and produce shorten CFTR protein, which was also first validated by in vitro truncation assay in this study. The missense variant c.1810A > C was predicted to disrupt the function of the nucleotide-binding domain 1 (NBD1) in the CFTR protein. The splicing variant c.1766 + 5G > T caused skipping of exon 13 and damaged the integrity of CFTR protein.
CONCLUSIONS: Our study expands the spectrum of phenotypes and genotypes for CF of Chinese origin, which differs significantly from that of Caucasian. Genetic analysis and counseling are crucial and deserve extensive popularization for the diagnosis ofCF in patients of Chinese origin.

UNASSIGNED: Intellectual disability (ID) is a clinically and genetically heterogeneous disorder. It drastically affects the learning capabilities of patients and eventually reduces their IQ level below 70.
UNASSIGNED: The current genetic study ascertained two consanguineous Pakistani families suffering from autosomal recessive intellectual developmental disorder-5 (MRT5). We have used exome sequencing followed by Sanger sequencing to identify the disease-causing variants.
UNASSIGNED: Genetic analysis using whole exome sequencing in these families identified two novel mutations in the NSUN2 (NM_017755.5). Family-A segregated a novel missense variant c.953A>C; p.Tyr318Ser in exon-9 of the NSUN2. The variant substituted an amino acid Tyr318, highly conserved among different animal species and located in the functional domain of NSUN2 known as \"SAM-dependent methyltransferase RsmB/NOP2-type\". Whereas in family B, we identified a novel splice site variant c.97-1G>C that affects the splice acceptor site of NSUN2. The identified splice variant (c.97-1G>C) was predicted to result in the skipping of exon-2, which would lead to a frameshift followed by a premature stop codon (p. His86Profs*16). Furthermore, it could result in the termination of translation and synthesis of dysfunctional protein, most likely leading to nonsense-mediated decay. The dynamic consequences of NSUN2 missense variant was further explored together with wildtype through molecular dynamic simulations, which uncovered the disruption of NSUN2 function due to a gain in structural flexibility. The present molecular genetic study further extends the mutational spectrum of NSUN2 to be involved in ID and its genetic heterogeneity in the Pakistani population.

Patients with DEX (deficiency in ELF4, X-linked) were recently reported by our team and others, and cases are very limited worldwide. Our knowledge of this new disease is currently preliminary. In this study, we described 5 more cases presenting mainly with oral ulcer, inflammatory bowel disease-like symptoms, fever of unknown origin, anemia, or systemic lupus erythematosus. Whole exome sequencing identified potential pathogenic ELF4 variants in all cases. The pathogenicity of these variants was confirmed by the detection of ELF4 expression in peripheral blood mononuclear cells from patients and utilizing a simple IFN-b luciferase reporter assay, as previously reported. Our findings significantly contribute to the current understanding of DEX.

PRPH2 gene mutations are frequently found in inherited retinal dystrophies (IRD) and are associated with a wide spectrum of clinical phenotypes. We studied 28 subjects affected by IRD carrying pathogenic PRPH2 mutations, belonging to 11 unrelated families. Functional tests (best-corrected visual acuity measurement, chromatic test, visual field, full-field, 30 Hz flicker, and multifocal electroretinogram), morphological retino-choroidal imaging (optical coherence tomography, optical coherence tomography angiography, and fundus autofluorescence), and clinical data were collected and analyzed. Common primary complaints, with onset in their 40s, were visual acuity reduction and abnormal dark adaptation. Visual acuity ranged from light perception to 20/20 Snellen. Visual field peripheral constriction and central scotoma were found. Chromatic sense was reduced in one third of patients. Electrophysiological tests were abnormal in most of the patients. Choroidal neovascular lesions were detected in five patients. Three novel PRPH2 variants were found in four different families. Based on the present multimodal study, we identified seven distinct PRPH2 phenotypes in 11 unrelated families carrying either different mutations or the same mutation, both within the same family or among them. Fundus autofluorescence modality turned out to be the most adequate imaging method for early recognition of this dystrophy, and the optical coherence tomography angiography was highly informative to promptly detect choroidal neovascularization, even in the presence of the extensive chorioretinal atrophy phenotype.

Fabry disease (FD) is a X-linked inherited disorder caused by mutations in the GLA gene, which results in the deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause multisystemic dysfunction. A recent screening study among neonates reported an increase in the incidence of FD, and numerous FD patients remain undiagnosed or even misdiagnosed. Therefore, this study aimed to identify patients with FD by performing high-risk screening in 18,135 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all prefectures in Japan. A total of 601 hospitals participated in this study.
Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request, and 12 of them were diagnosed with a variant of FD. A total of 236 patients with FD (97 males and 139 females) were identified from among 18,199 participants. A total of 101 GLA variants, including 26 novel variants, were detected in the 236 patients with FD from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment.
From among 18,199 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 patients with FD from 143 families. Migalastat was identified as a suitable treatment option in 33% of the patients with FD and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol using dried blood spots that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients with various renal, cardiac, or neurological manifestations.

The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical assessment, which includes clinical history and analysis with multimodal retinal imaging, electrophysiology, and visual field testing. If suitable for recruitment, a sample is taken and used for genetic analysis. Genetic analysis is conducted by use of a retinal gene panel target capture sequencing approach. With over 1000 participants from 710 pedigrees now screened, there is a positive candidate variant detection rate of approximately 70% (495/710). Where an autosomal recessive inheritance pattern is observed, an additional 9% (64/710) of probands have tested positive for a single candidate variant. Many novel variants have also been detected as part of this endeavor. The target capture approach is an economic and effective means of screening patients with inherited retinal disorders. Despite the advances in sequencing technology and the ever-decreasing associated processing costs, target capture remains an attractive option as the data produced is easily processed, analyzed, and stored compared to more comprehensive methods. However, with decreasing costs of whole genome and whole exome sequencing, the focus will likely move towards these methods for more comprehensive data generation.

Oculocutaneous albinism is an autosomal recessive disorder characterized by either a complete lack of or reduction in melanin biosynthesis in the skin, hair, and eyes. The aim of the present study was to identify the molecular basis for 59 Chinese OCA families. In this study, compound heterozygous or homozygous pathogenic variants were found in 53 families, 4 families possessed only one heterozygous variant, and the pathogenic variants of 2 families remain undiscovered by using Sanger sequencing, whole exome sequencing and multiplex ligation-dependent probe amplification. We have identified a total of 55 variants including 21 novel variants in TYR, OCA2, SLC45A2, SLC24A5, and HPS1. The 21 novel variants include 11 missense changes, 4 nonsense changes, 2 splice site changes, 1 frameshift and 3 gross deletions. Forty-six variants including 14 novel variants were segregated with the phenotype in 37 families. We conducted RT-PCR of the novel splicing site variant (c.399-14G > A) of HPS1 and verified that the variant would result in the inclusion of 12 bp of intronic material in exon 6 of HPS1. The results of platelet whole mount electron microscopy further confirmed the diagnosis of HPS1. These novel variants identified in our study expand the mutational spectrum of the disease, which contributes to prenatal diagnosis and genetic counselling.

Alzheimer\'s disease (AD) is a chronic neurological disorder associated with mental decline and dementia. Several studies focused on investigating the molecular basis of the disease that led to the identification of several causative genes and risk associated alleles. Replication of these studies and findings from different populations is very important.
Molecular assessment of a cohort of 117 familial and sporadic AD cases from Saudi Arabia.
Comprehensive screening for point mutations was carried out by direct sequencing of coding regions in the three known AD causative genes: PSEN1, PSEN2, APP, as well as the AD associated gene SORL1. All patients were also genotyped for APOE alleles. In silico 3D protein structure analysis was performed for two novel SORL1 variants.
We identified a total of eight potential pathogenic missense variants in all studied genes. Five of these variants were not previously reported including four in SORL1 (p.Val297Met, p.Arg1084Cys, p.Asp1100Asn, and p.Pro1213Ser) and one in APP (p.Glu380Lys). The frequency of APOE-ɛ4 allele was 21.37% of total investigated cases. In silico 3D protein structure analysis of two SORL1 novel missense variants (p.Pro1213Ser and p.Arg1084Cys) suggested that these variants may affect the folding of the proteins and disturb their structure.
Our comprehensive analysis of the open reading frame of the known genes have identified potential pathogenic rare variants in 18/117 cases. We found that point mutations in AD main genes (PSEN1, PSEN2, and APP) were underrepresented in our cohort of patients. Our results confirm involvement of SORL1 in familial and sporadic AD cases.

Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P < 5 × 10-08 ), with the strongest association between rs651821:C>T in APOA5 and triglyceride levels (P  =  3.67 × 10-10 ). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.