Rare Pathogenic Variants Identified in Whole Exome Sequencing of Monozygotic Twins With Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a childhood-onset complex neurodevelopmental disorder characterized by problems with communication and social interaction and restricted, repetitive, stereotyped behavior. The prevalence of ASD is one in 36 children. The genetic architecture of ASD is complex in spite of its high heritability. To identify the potential candidate genes of ASD, we carried out a comprehensive genetic study of monozygotic (MZ) twins concordant or discordant for ASD. METHODS: Five MZ twins and their parents were recruited for the study. Four of the twins were concordant, whereas one was discordant for ASD. Whole exome sequencing was conducted for the twins and their parents. The exome DNA was enriched using Twist Human Customized Core Exome Kit, and paired-end sequencing was performed on HiSeq system. RESULTS: We identified several rare and pathogenic variants (homozygous recessive, compound heterozygous, de novo) in ASD-affected individuals. CONCLUSION: We report novel variants in individuals diagnosed with ASD. Several of these genes are involved in brain-related functions and not previously reported in ASD. Intriguingly, some of the variants were observed in the genes involved in sensory perception (auditory [MYO15A, PLEC, CDH23, UBR3, GPSM2], olfactory [OR9K2], gustatory [TAS2R31], and visual [CDH23, UBR3]). This is the first comprehensive genetic study of MZ twins in an Indian population. Further validation is required to determine whether these variants are associated with ASD.

A Comparative Genomic Analysis of Parathyroid Adenomas and Carcinomas Harboring Heterozygous Germline CDC73 Mutations.

CONTEXT: Parathyroid cancer has been linked to germline mutations of the CDC73 gene. However, carriers harboring cancer-associated germline CDC73 mutations may develop only parathyroid adenoma or no parathyroid disease. This incomplete penetrance indicates that additional genomic events are required for parathyroid tumorigenesis. OBJECTIVE: (1) Determine the status of the second CDC73 allele in parathyroid tumors harboring germline CDC73 mutations, and (2) compare the genomic landscapes between parathyroid carcinomas and adenomas. DESIGN: Whole-exome and RNA sequencing of 12 parathyroid tumors harboring germline CDC73 mutations (6 adenomas and 6 carcinomas) and their matched normal tissues. RESULTS: All 12 parathyroid tumors had gained one somatic event predicted to cause a complete inactivation of the second CDC73 allele. Several distinctive genomic features were identified in parathyroid carcinomas compared to adenomas, including more single nucleotide variants bearing the C>G transversion and APOBEC deamination signatures, frequent mutations of the genes involved in the PI-3K/mTOR signaling, a greater number of copy number variations, and substantially more genes with altered expression. Parathyroid carcinomas also share some genomic features with adenomas. For instance, both have recurrent somatic mutations and copy number loss that impact the genes involved in T-cell receptor signaling and tumor antigen presentation, suggesting a shared strategy to evade immune surveillance. CONCLUSIONS: Biallelic inactivation of CDC73 is essential for parathyroid tumorigenesis in carriers harboring germline mutations of this gene. Despite sharing some genomic features with adenomas, parathyroid carcinomas have more distinctive alterations in the genome, some of which may be critical for cancer formation.

A de novo ARIH2 gene mutation was detected in a patient with autism spectrum disorders and intellectual disability.

E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular processes. As prior documented, mutations in genes involved in the ubiquitination process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In the current study, a de novo heterozygous mutation was identified in the splicing intronic region adjacent to the last exon of the ARIH2 gene using whole exome sequencing (WES). We hypothesize that this mutation, found in an ASD/ID patient, disrupts the protein Ariadne domain which is involved in the autoinhibition of ARIH2 enzyme. Predictive analyses elucidated the implications of the novel mutation in the splicing process and confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude the possibility that other genetic factors, undetectable by WES, such as mutations in non-coding regions and polygenic risk in inter-allelic complementation, may contribute to the patient's phenotype. This work aims to suggest potential relationship between the detected mutation in ARIH2 gene and both ASD and ID, even though functional studies combined with new sequencing approaches will be necessary to validate this hypothesis.

Pathogenic relationship between phenotypes of ARPKD and novel compound heterozygous mutations of PKHD1.

Background: To investigate whether the novel mutation of PKHD1 could cause polycystic kidney disease by affecting splicing with a recessive inheritance pattern. Methods: A nonconsanguineous Chinese couple with two recurrent pregnancies showed fetal enlarged echogenic polycystic kidney and oligoamnios were recruited. Pedigree WES, minigene splicing assay experiment and following bioinformatics analysis were performed to verify the effects, and inheritance pattern of diseasing-causing mutations. Results: WES revealed that both fetuses were identified as carrying the same novel mutation c.3592_3628 + 45del, p.? and c.11207 T>C, p.(Ile3736Thr) in the PKHD1 gene (NM_138694.4), which inherited from the father and mother respectively. Both bioinformatic method prediction and minigene splicing assay experience results supported the mutation c.3592_3628 + 45del, p.? affects the splicing of the PKHD1 transcript, resulting in exon 31 skipping. Another missense mutation c.11207 T>C, p.(Ile3736Thr) has a low frequency in populations and is predicted to be deleterious by bioinformatic methods. Conclusion: These findings provide a direct clinical and functional evidence that the truncating mutations of the PKHD1 gene could lead to more severe phenotypes, and cause ARPKD as a homozygous or compound heterozygous pattern. Our study broadens the variant spectrum of the PKHD1 gene and provides a basis for genetic counseling and diagnosis of ARPKD.

Genetic change investigation in DOCK1 gene in an Iranian family with sign and symptoms of temporomandibular joint disorder (TMD).

OBJECTIVES: Temporomandibular joint disorder (TMD) is a complex condition with pain and dysfunction in the temporomandibular joint and related muscles. Scientific evidence indicates both genetic and environmental factors play a crucial role in TMD. In this study, we aimed to discover the genetic changes in individuals from 4 generations of an Iranian family with signs and symptoms of TMD and malocclusion Class III. MATERIALS AND METHODS: Whole Exome Sequencing (WES) was performed in 4 patients (IV-8, IV-9, V-4, and V-6) with TMD according to (DC/TMD), along with skeletal Class III malocclusion. Then, PCR sequencing was performed on 23 family members to confirm the WES. RESULTS: In the present study, WES results analysis detected 6 heterozygous non-synonymous Single Nucleotide Variants (SNVs) in 5 genes, including CRLF3, DNAH17, DOCK1, SEPT9, and VWDE. A heterozygous variant, c.2012T > A (p.F671Y), in Exon 20 of the DOCK1 (NM_001290223.2) gene was identified. Then, this variant was investigated in 19 other members of the same family. PCR-Sequencing results showed that 7/19 had heterozygous TA genotype, all of whom were accompanied by malocclusion and TMD symptoms and 12/19 individuals had homozygous TT genotype, 9 of whom had no temporomandibular joint problems or malocclusion. The remaining 3 showed mild TMD clinical symptoms. The 5 other non-synonymous SNVs of CRLF3, DNAH17, SEPT9, and VWDE were not considered plausible candidates for TMD. CONCLUSIONS: The present study identified a heterozygous nonsynonymous c.2012T > A (p.F671Y) variant of the DOCK1 gene is significantly associated with skeletal class III malocclusion, TMD, and its severity in affected individuals in the Iranian pedigree. CLINICAL RELEVANCE: The role of genetic factors in the development of TMD has been described. The present study identified a nonsynonymous variant of the DOCK1 gene as a candidate for TMD and skeletal class III malocclusion in affected individuals in the Iranian pedigree.

Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma.

Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole-exome sequencing of laser-capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK-RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. Prognostic associations were found for CDC27, LRP2, APC, and SNAPC4. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.

Impact of high-risk EBV strains on nasopharyngeal carcinoma gene expression.

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr Virus infection (EBV). Despite ubiquitous EBV infection worldwide, NPC displays a unique geographical distribution in Southern China and Southeast Asia. This observed phenomenon can be attributed to the interplay of different strains of EBV infection with host genetics and environmental factors. Polymorphisms on the EBV BALF2 gene have been shown to influence risk of nasopharyngeal carcinoma (NPC). Notably, two non-synonymous EBV polymorphisms (162476T>C, 163364C>T) account for majority of NPC risk in endemic regions. These polymorphisms confer amino acid changes (I1613V, V317M) within the BALF2 protein. However, their impact on NPC tumor biology is unknown. We evaluated the distribution of BALF2 risk polymorphisms in five independent genomic datasets comprising 351 NPC clinical samples, confirming the high prevalence of high-risk EBV strains in NPC. Importantly, we observed two biologically distinct groups of tumors based on their gene expression profiles when grouped by their EBV risk strains. NPC tumors with the V317M substitution demonstrated increased proliferation processes including cell cycle (NES = 1.71, p = 5.64x10-24) and keratinization (NES = 2.42, p = 6.95x10-17). In contrast, NPC tumors without the V317M substitution demonstrated increased immune-related processes, including cell activation (NES = 1.85, p = 8.29x10-31), myeloid leukocyte activation (NES = 2.16, p = 6.51x10-24) and leukocyte mediated immunity (NES = 1.99, p = 1.05x10-23). These findings provide further insight on the influence of BALF2 variants on NPC tumor biology. EBV risk strains may have the potential to define biologically important groups in NPC.

Effectiveness of whole exome sequencing analyses in the molecular diagnosis of osteogenesis imperfecta.

OBJECTIVES: Osteogenesis imperfecta (OI) is a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. This study aimed to investigate the molecular genetic etiology and to determine the relationship between genotype and phenotype in OI patients with whole exome sequencing (WES). METHODS: Multiplex-Ligation dependent Probe Amplification (MLPA) analysis of COL1A1 and COL1A2 and WES were performed on cases between the ages of 0 and 18 whose genetic etiology could not be determined before using a targeted next-generation sequencing panel, including 13 genes (COL1A1, COL1A2, IFITM5, SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, SP7, BMP1, MBTPS2, PLOD2) responsible for OI. RESULTS: Twelve patients (female/male: 4/8) from 10 different families were included in the study. In 6 (50 %) families, consanguineous marriage was noted. The clinical typing based on Sillence classification; 3 (25 %) patients were considered to be type I, 7 (58.3 %) type III, and 2 (16.7 %) type IV. Deletion/duplication wasn't detected in the COL1A1 and COL1A2 genes in the MLPA analysis of the patients. Twelve patients were molecularly analyzed by WES, and in 6 (50 %) of them, a disease-causing variant in three different genes (FKBP10, P3H1, and WNT1) was identified. Two (33.3 %) detected variants in all genes have not been previously reported in the literature and were considered deleterious based on prediction tools. In 6 cases, no variants were detected in disease-causing genes. CONCLUSIONS: This study demonstrates rare OI types' clinical and molecular features; genetic etiology was determined in 6 (50 %) 12 patients with the WES analysis. In addition, two variants in OI genes have been identified, contributing to the literature.

Novel PATL2 variants cause female infertility with oocyte maturation defect.

PURPOSE: Oocyte maturation defect (OOMD) is a rare cause of in vitro fertilization failure characterized by the production of immature oocytes. Compound heterozygous or homozygous PATL2 mutations have been associated with oocyte arrest at the germinal vesicle (GV), metaphase I (MI), and metaphase II (MII) stages, as well as morphological changes. METHODS: In this study, we recruited three OOMD cases and conducted a comprehensive multiplatform laboratory investigation. RESULTS: Whole exome sequence (WES) revealed four diagnostic variants in PATL2, nonsense mutation c.709C > T (p.R237*) and frameshift mutation c.1486_1487delinsT (p.A496Sfs*4) were novel mutations that have not been reported previously. Furthermore, the pathogenicity of these variants was predicted using in silico analysis, which indicated detrimental effects. Molecular dynamic analysis suggested that the A496S variant disrupted the hydrophobic segment, leading to structural changes that affected the overall protein folding and stability. Additionally, biochemical and molecular experiments were conducted on cells transfected with wild-type (WT) or mutant PATL2 (p.R237* and p.A496Sfs*4) plasmid vectors. CONCLUSIONS: The results demonstrated that PATL2A496Sfs*4 and PATL2R237* had impacts on protein size and expression level. Interestingly, expression levels of specific genes involved in oocyte maturation and early embryonic development were found to be simultaneously deregulated. The findings in our study expand the variation spectrum of the PATL2 gene, provide solid evidence for counseling on future pregnancies in affected families, strongly support the application of in the diagnosis of OOMD, and contribute to the understanding of PATL2 function.

High prevalence of ALPK3 premature terminating variants in Korean hypertrophic cardiomyopathy patients.

Background: The alpha-protein kinase 3 (ALPK3) gene (OMIM: 617608) is associated with autosomal recessive familial hypertrophic cardiomyopathy-27 (CMH27, OMIM: 618052). Recently, several studies have shown that monoallelic premature terminating variants (PTVs) in ALPK3 are associated with adult-onset autosomal dominant hypertrophic cardiomyopathy (HCMP). However, these studies were performed on patient cohorts mainly from European Caucasian backgrounds. Methods: To determine if this finding is replicated in the Korean HCMP cohort, we evaluated 2,366 Korean patients with non-syndromic HCMP using exome sequencing and compared the cohort dataset with three independent population databases. Results: We observed that monoallelic PTVs in ALPK3 were also significantly enriched in Korean patients with HCMP with an odds ratio score of 10-21. Conclusions: We suggest that ALPK3 PTV carriers be considered a risk group for developing HCMP and be monitored for cardiomyopathies.

Identification of LAMA2 compound heterozygous variants: a case report.

Background: Laminin-α2 (LAMA2) chain-deficient muscular dystrophy (LAMA2-MD) is the most common congenital muscular dystrophy (CMD) in the world. Its main manifestations are muscle weakness and hypotonia that occur after birth or at early infancy. Case Description: We reported a case of a 3-year-old and 6-month-old boy presented with delayed motor development, elevated creatine kinase (CK) levels, and abnormal white matter in the brain. Whole exome sequencing (WES) showed compound heterozygous variants of the LAMA2 gene. This case reports for the first time the compound heterozygous LAMA2 variants c.5476C>T (p.R1826*) (paternal inheritance) with c.2749 + 2dup (maternal inheritance), as both variants are interpreted as pathogenic/potentially pathogenic variants. Conclusions: This study reports a novel heterozygous variant, including two pathogenic variants in the LAMA2 gene, and highlights the effectiveness of highly efficient exome sequencing applying in patients with undefined CMDs.

Comparative analysis of genetic variants in pleural fluids and solid tissue biopsies of pleural mesothelioma patients: Implications for molecular heterogeneity assessment.

Objectives: This study aims to determine whether the sequencing of DNA extracted from pleural fluids (PFs) of Pleural Mesothelioma (PM) patients accurately represents the genetic information obtained from the solid tissue counterpart biopsies with particular attention to the identification of single nucleotide variants (SNVs). Materials and methods: Single pleural biopsy, PFs, and blood were collected from PM patients. DNA was extracted from these samples and then subjected to Whole-Exome Sequencing. Results: A higher number of SNVs was identified in PFs than in solid tissue biopsies (STBs). Most SNVs were detected in PFs samples but not in STBs samples, while only a few SNVs were detected in STBs samples but not in PFs samples. Conclusion: The current findings support the notion that PFs might offer a more robust depiction of cancer's molecular diversity. Nonetheless, the current outcomes challenge the assertion that liquid biopsies can encompass the entirety of intra-patient variations. Indeed, a subset of potential cancer-driver SNVs was exclusively identified in STBs. However, relying solely on STBs would have precluded the detection of significant SNVs that were exclusively present in PFs. This implies that while PFs serve as a valuable complement to STBs, they do not supplant them.

Novel genotypes and phenotypes in Snijders Blok-Campeau syndrome caused by CHD3 mutations.

Background: Snijders Blok-Campeau syndrome (SNIBCPS) is a rare genetic disorder characterized by facial abnormalities, hypotonia, macrocephaly, and global developmental delay (GDD) caused by mutations in CHD3 gene. There is limited information on SNIBCPS and few studies on its pathogenic gene CHD3. Methods: We utilized whole-exome sequencing, in vitro minigene splicing assay analysis, and construction of protein models to validate the suspected pathogenic mutation. In addition, the PubMed database was searched using the keywords "Snijders Blok-Campeau syndrome," "CHD3," or "SNIBCPS" to summarize the gene mutations and clinical phenotypic characteristics of children with SNIBCPS. Results: We identified a non-frameshift variant c.3592_c.3606delGCCAAGAGAAAGATG, a splice site variant c.1708-1G>T, and two missense variants, c. 2954G>C (p.Arg985Pro) and c.3371C>T (p.A1124V), in CHD3 variants with SNIBCPS. Importantly, the c.3592_c.3606delGCCAAGAGAAAGATG, c.1708-1G>T, and c.3371C > T (p.A1124V) loci were not reported, and the children in this study also had phenotypic features of unibrow, transverse palmar creases, tracheal bronchus, and hypomelanosis of Ito (HI). The c.1708-1G>T classical splicing mutation leads to abnormal shearing of mRNA, forming a truncated protein that ultimately affects gene function. Conclusion: Our findings have expanded the spectrum of genetic variants and clinical features in children with SNIBCPS. Splicing analysis of CHD3 is an important method to understand the pathogenesis of spliced cells.

Whole-Exome Sequencing Identifies Germline BLM Mutation in Ovarian Hepatoid Adenocarcinoma with Favorable Response to Niraparib and Anlotinib Combination Therapy-A Case Report and Literature Review.

Hepatoid adenocarcinoma of the ovary represents a rare and malignant extrahepatic tumor that shares morphological and immunophenotypic similarities with hepatocellular carcinoma. Due to the ambiguous histomorphology and aggressive behavior, the diagnosis and management of hepatoid adenocarcinoma of the ovary present unique challenges. Here, we present a 67-year-old woman with massive ascites and disseminated peritoneal implants at initial diagnosis. She was treated with six cycles of neoadjuvant therapy (albumin-bound paclitaxel + nedaplatin + bevacizumab) and a debulking surgery, followed by eight cycles of postoperative adjuvant therapy (albumin-bound paclitaxel + carboplatin + bevacizumab). Elaborate pathology workup found significant involvement of angiogenesis in the tumor and confirmed the diagnosis via immunohistochemistry. Further molecular characterization of the tumor by whole-exome sequencing (WES) revealed a novel heterozygous germline mutation (NM_000057.2, c.1290_1291delinsATCAGGCCTCCATAG, p.Y430fs1) in gene BLM, likely pathogenic, suggesting a potential candidate for Poly (ADP-ribose) polymerase (PARP) inhibitors. For the maintenance therapy, she received a combination of the PARP inhibitor niraparib and the antiangiogenic anlotinib. As of now, the patient has achieved a partial response, with no apparent evidence of disease progression observed nearly 30 months. Our study sheds light on the WES-based profiling in rare cancers to screen for any treatable targets with otherwise no standard therapeutic options. The promising results with the niraparib-anlotinib combination suggest its potential as a maintenance therapy option for hepatoid adenocarcinoma of the ovary, which warrants validation in future larger cohort.

Dystrophic epidermolysis bullosa characterized by mucosal lesions in a Chinese familial case with a novel compound heterozygous mutation of COL7A1.

Dystrophic epidermolysis bullosa (DEB) is a rare, but severe, subtype of epidermolysis bullosa. It is characterized mainly by blisters and miliary rashes of the skin, while oral mucosa-dominated cases are extremely rare. Here, we report the characteristics of oral mucosa lesions in a Chinese familial case of DEB with a novel compound heterozygous COL7A1 mutation. We further analyzed the genetic and molecular features of the proband and the two related mutation carriers. Our study further elucidates the genetic and phenotypic heterogeneity of DEB.

Nablus mask-like facial syndrome: Report of an atypical case with 8q21.3-q22.1 deletion.

Nablus mask-like facial syndrome (NMLFS) is a rare condition characterized by unique facial features, initially described in a 4-year-old boy from Nablus, Palestine. These features include expressionless facial appearance, tight facial skin, blepharophimosis, sparse eyebrows, and a flat nose. Genetic studies have identified a deletion of 8q22.1 as the cause of the syndrome, however while 26 patients have been reported with the deletion, only 13 displayed the characteristic facial features. Here we report on a 35-year-old male with 8q21.3-q22.1 deletion identified by whole exome sequencing and Chromosomal microarray analysis (CMA) that presents with typical and atypical features, including neurodevelopmental disorder, mild facial features, and myopathy, which has not been described in a patient with NMLFS to date. Further research will be required to understand the underlying pathogenetic mechanism of this rare genetic disorder.

Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia.

BACKGROUND: Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we applied the whole exome sequencing (WES) to find the cause of HL and COD in an Iranian consanguineous family with three affected individuals. METHODS: Three members from an Iranian consanguineous family who were suffering from NSHL and visual impairment were ascertained in this study. Comprehensive clinical evaluations and genetic analysis followed by bioinformatic and co-segregation studies were performed to diagnose the cause of these phenotypes. Data were collected from 2020 to 2022. RESULTS: All cases showed congenital bilateral NSHL, decreased visual acuity, poor color discrimination, photophobia and macular atrophy. Moreover, cornea, iris and anterior vitreous were within normal limit in both eyes, decreased foveal sensitivity, central scotoma and generalized depression of visual field were seen in three cases. WES results showed two variants, a novel null variant (p.Trp548Ter) in the PDE6C gene causing COD type 4 (Achromatopsia) and a previously reported variant (p.Ile84Thr) in the PDZD7 gene causing NSHL. Both variants were found in the cis configuration on chromosome 10 with a genetic distance of about 8.3 cM, leading to their co-inheritance. However, two diseases could appear independently in subsequent generations due to crossover during meiosis. CONCLUSIONS: Here, we could successfully determine the etiology of a seemingly complex phenotype in two adjacent genes. We identified a novel variant in the PDE6C gene, related to achromatopsia. Interestingly, this variant could cooperatively cause visual disorders: cone dystrophy and cone-rod dystrophy.

Effect of the OPHN1 novel variant c.1025+1 G>A on RNA splicing: insights from a minigene assay.

This research analyzes the clinical data, whole-exome sequencing results, and in vitro minigene functional experiments of a child with developmental delay and intellectual disability. The male patient, aged 4, began experiencing epileptic seizures at 3 months post-birth and has shown developmental delay. Rehabilitation training was administered between the ages of one and two. There were no other significant family medical histories. Through comprehensive family exome genetic testing, a hemizygous variant in the 11th exon of the OPHN1 gene was identified in the affected child: c.1025 + 1G > A. Family segregation analysis confirmed the presence of this variant in the patient's mother, which had not been previously reported. According to the ACMG guidelines, this variant was classified as a likely pathogenic variant. In response to this variant, an in vitro minigene functional experiment was designed and conducted, confirming that the mutation affects the normal splicing of the gene's mRNA, resulting in a 56 bp retention on the left side of Intron 11. It was confirmed that OPHN1: c.1025 + 1G > A is the pathogenic cause of X-linked intellectual disabilities in the child, with clinical phenotypes including developmental delay and seizures.

Hereditary coagulation factor VII deficiency caused by novel compound heterozygous mutations c.572-1G>A and c.1037A>C in a Chinese pedigree.

Hereditary coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder. The aims of this study were to identify and verify the pathogenic mutations sites in a family with hereditary coagulation FVII deficiency, and preliminarily explore the underlying mechanisms. We identified a novel combination of compound heterozygous mutations, c.572-1G>A and c.1037A>C in F7 gene, associated with FVII deficiency. The splice site mutation c.572-1G>A led to a truncation, resulting in the loss of the essential catalytic domain of the FVII protein. The c.1037A>C missense mutation has not been previously reported. Our study revealed that this mutation leads to steric hindrance between residues, causing significant changes in the energy and structure of the FVII protein, ultimately affecting its function. These changes disrupt the normal function of the FVII protein, accelerating the development of inherited FVII deficiency. Moreover, the mRNA expression of the F7 gene and the protein expression of the FVII antigen (FVII: Ag) were significantly lower in the proband, as well as in their parents, compared to the healthy control (P<0.05). Our findings not only elucidate the genetic underpinning of FVII deficiency in the family studied but also contribute a new mutation to the known disease spectrum, potentially assisting in future diagnostic and therapeutic approaches.

Whole-Exome Sequencing Detecting a Recurrent Pathogenic Mutation, HFE p.His63Asp (H63D) in COVID-19 Patients and Its Effect on Mortality.

BACKGROUND: In recent years, various coronaviruses have caused severe respiratory illnesses worldwide. For example the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections of COVID-19 outbreak in 2019 in Wuhan, China. Genome-wide association studies (GWAS) have significantly expanded our comprehension of how specific genetic variations are linked to diseases. Research has demonstrated the existence of genetic factors influencing susceptibility to coronaviruses. The objective of this study was to examine the association of certain loci with the COVID-19 in Saudi population. METHODS: In the present study we have examined the link between the COVID-19 disease and certain genetic variants in hospitalized COVID-19 patients (n = 16) in Tabuk and Bisha, Kingdom Saudi Arabia. We used the genome Analysis Toolkit (GATK) and Comprehensive variant annotation was performed different databases and tools such as Search Tool for the Retrieval of Interacting Genes (STRING), PanelApp and PolyPhen-2. RESULTS: The study showed that the genetic variants associated with genes such as Homeostatic Iron Regulator (HFE) (found in 7 patients, representing 44%), complement factor H (CFH) (6 patients, 38%), cadherin 23 (CDH23) (4 patients, 25%), cytotoxic T-lymphocyte associated protein 4 (CTLA-4) (3 patients, 19%), Transforming Growth Factor Beta 1 (TGFB1) (3 patients, 19%), CREB-binding protein (CREBBP) (2 patients, 13%), E1A Binding Protein P300 (EP300) (2 patients, 13%), hemoglobin subunit beta (HBB) (2 patients, 13%), interferon regulatory factor 7 (IRF7) (2 patients, 13%), and unc-119 lipid binding chaperone (UNC119) (2 patients, 13%) might be associated with susceptibility to coronavirus. We also identified mutations in the COVID-19 patient that are pathogenic or likely pathogenic. CONCLUSION: A recurrent pathogenic mutation, HFE p.His63Asp (H63D), was identified in 7 patients, suggesting its potential contribution to disease severity. Additionally, a likely pathogenic variant, HBB p.Glu7Val (E7V), was present in 2 patients, highlighting its potential role in disease susceptibility. Our results shed light on the key genetic mechanisms of COVID-19 pathogenesis and help to identify and stratify the individuals or populations that are at risk to corona virus infection. The identification of susceptible individuals or populations assist in prevention and/or in treatment programs.