The polysialyltransferases ST8SIA2 and ST8SIA4 and their product, polysialic acid (polySia), are known to be related to cancers and mental disorders. ST8SIA2 and ST8SIA4 have conserved amino acid (AA) sequence motifs essential for the synthesis of the polySia structures on the neural cell adhesion molecule. To search for a new motif in the polysialyltransferases, we adopted the in silico Individual Meta Random Forest program that can predict disease-related AA substitutions. The Individual Meta Random Forest program predicted a new eight-amino-acids sequence motif consisting of highly pathogenic AA residues, thus designated as the pathogenic (P) motif. A series of alanine point mutation experiments in the pathogenic motif (P motif) showed that most P motif mutants lost the polysialylation activity without changing the proper enzyme expression levels or localization in the Golgi. In addition, we evaluated the enzyme stability of the P motif mutants using newly established calculations of mutation energy, demonstrating that the subtle change of the conformational energy regulates the activity. In the AlphaFold2 model, we found that the P motif was a buried β-strand underneath the known surface motifs unique to ST8SIA2 and ST8SIA4. Taken together, the P motif is a novel buried β-strand that regulates the full activity of polysialyltransferases from the inside of the molecule.

UNASSIGNED: Genetic and acquired risk factors are fundamental to developing venous thromboembolism. Autosomal dominant protein S deficiency caused by pathogenic mutations in the PROS1 gene is a well-known risk factor for thrombophilia.
UNASSIGNED: We report a 30-year-old male patient who presented to the hospital with portal vein thrombosis. The patient had a history of abdominal pain for one month. Abdominal vascular CT showed venous thrombosis in the portal vein and superior mesenteric vein. He was diagnosed with \"portal and superior mesenteric vein thrombosis, small bowel obstruction and necrosis, acute upper gastrointestinal bleeding (UGIB), hemorrhagic shock.\" Serum protein S levels were decreased, and gene sequencing revealed a heterozygous missense mutation in PROS1, c.1571T > G (p.Leu584Arg). The patient received anticoagulation therapy with Enoxaparin Sodium and rivaroxaban, transjugular intrahepatic portosystemic shunt (TIPS), and ICU treatments. Although the patient had a severe bleeding event during anticoagulation therapy, he recovered well after active treatment and dynamic monitoring of anti-Xa.
UNASSIGNED: Hereditary protein S deficiency caused by a mutation in the PROS1 gene is the genetic basis of this patient, and Enoxaparin Sodium and rivaroxaban have been shown to be highly effective.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. The primary objective of this study was to identify the major pathogenic mutations in a Chinese family with FH.
METHODS: Whole-genome sequencing (WGS) was used to identify variants of FH-related genes, including low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). Bioinformatics software was used to predict signal peptides, transmembrane structures, and spatial construction information of the mutated sequences. Western blotting was performed on the mutant protein to determine the presence of the major structural domains of the LDLR. The PCSK9 and APOB genes were screened and analyzed. Moreover, the proband and his brother were treated with a PCSK9 inhibitor for 1 year, and the effect of the treatment on lipid levels was assessed.
RESULTS: WGS revealed two potentially pathogenic mutations in the LDLR gene. One was a novel mutation, c.497delinsGGATCCCCCAGCTGCATCCCCCAG (p. Ala166fs), and the other was a known pathogenic mutation, c.2054C>T (p. Pro685Leu). Bioinformatics prediction and in vitro experiments revealed that the novel mutation could not be expressed on the cell membrane. Numerous gene variants were identified in the APOB gene that may have a significant impact on the family members with FH. Thus, it is suggested that the severe manifestation of FH in the proband primarily resulted from the cumulative genetic effects of variants in both LDLR and APOB. However, a subsequent study indicated that treatment with a PCSK9 inhibitor (Evolocumab) did not significantly reduce the blood lipid levels in the proband or his brother.
CONCLUSIONS: The cumulative effect of LDLR and APOB variants was the primary cause of elevated blood lipid levels in this family. However, PCSK9 inhibitor therapy did not appear to be beneficial for the proband. This study emphasizes the importance of genetic testing in determining the most suitable treatment options for patients with FH.

UNASSIGNED: triple-negative breast cancer (TNBC) is a heterogeneous breast cancer type with a poor prognosis. About 25% of TNBC patients carry breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) mutations. Screening for BRCA mutations would facilitate early detection and initiation of personalized therapy, thus improving prognosis. However, this has not been explored in our population. We aimed at identifying BRCA1 and BRCA2 gene mutations and their clinical relevance among selected women with TNBC in Kenya.
UNASSIGNED: six participants enrolled in a larger descriptive cross-sectional study who met the inclusion criteria were selected. Structured questionnaires were used to obtain qualitative data. Deoxyribonucleic acid (DNA) was extracted from saliva. Whole exome sequencing of BRCA1 and BRCA2 genes using a next-generation sequencer was done.
UNASSIGNED: overall, 83.3% of BRCA1 and BRCA2 gene mutations with clinical relevance were detected. Most of the variants (63%) were found in BRCA1 whereas 37% were found in BRCA2. Pathogenic mutations in BRCA1 gene included c.5513T>A, c.5291T>C, c.5297T>G, c.110C>A, c.5212G>C, c.122A>C, c.5117G>A, c.5095C>T, c.5054C>T, c.5053A>G, c.115T>A, c.5143A>G, and c.130T>G. Those in BRCA2 gene were c.7878G>A, c.9154C>T, c.8243G>A, c.7976G>A, c.8165C>G, c.8167G>C, and c.8168A>T. One variant (c.5352delG: p. Leu1785Terfs) not matching any in the BRCA Exchange and ClinVar databases was detected.
UNASSIGNED: our study revealed BRCA mutations that could be common among our population. Further, it has shown that BRCA1 and BRCA2 genetic mutations identified are of clinical relevance and there is a need to screen for these mutations in breast cancer patients to understand their implication in patient management outcomes.

More than 25 million DNA variations have been discovered as novel including major alleles from the Arab population. Exome studies on the Saudi genome discovered > 3000 novel nucleotide variants associated with > 1200 rare genetic disorders. Reclassification of many pathogenic variants in the Human Gene Mutation Database and ClinVar Database as benign through the Arab database facilitates building a detailed and comprehensive map of the human morbid genome. Intellectual disability comes first with the combined and observed carrier frequency of 0.06779 among Saudi Arabians; retinal dystrophy is the next highest. Genome studies have discovered interesting novel candidate disease marker variations in many genes from consanguineous families. More than 7 pathogenic variants in the C12orf57 gene are prominently associated with the etiology of developmental delay/intellectual impairment in Arab ancestries. Advances in large-scale genome studies open a new outlook on Mendelian genes and disorders. In the past half-dozen years, candidate genes of intellectual disability, neurogenetic disorders, blood and bleeding disorders and rare genetic diseases have been well documented through genomic medicine studies in combination with advanced computational biology applications. The Arab mitogenome exposed hundreds of variations in the mtDNA genome and ancestral sharing with Africa, the Near East and East Asia and its association with obesity. These recent discoveries in disease markers and molecular genetics of the Arab population will have a positive impact towards supporting genetic counsellors on reaching consanguineous families to manage stress linked to genetics and precision medicine. This narrative review summarizes the advances in molecular medical genetics and recent discoveries on pathogenic variants. Despite the fact that these initiatives are targeting the genetics and genomics of disorders prevalent in Arab populations, a lack of complete cooperation across the projects needed to be revisited to uncover the Arab population\'s prominent disease markers. This shows that further study is needed in genomics to fully comprehend the molecular abnormalities and associated pathogenesis that cause inherited disorders in Arab ancestries.

UNASSIGNED: This article analyzes 2 practice patterns our institution uses for genetic testing of patients with inherited retinal diseases (IRDs) and compares testing completion and diagnostic yield rates.
UNASSIGNED: A retrospective, consecutive chart review series was conducted of patients with a clinically diagnosed rod-mediated IRD. All IRDs were diagnosed between 2 intervals: November 1, 2015, through November 30, 2016 (referral to a medical genetics clinic for testing) or December 1, 2016, through December 30, 2017 (same-day, in-office genetic testing).
UNASSIGNED: A total of 189 patients were included in the study. Of patients who received an out-of-office referral for genetic testing, 10 of 84 (12%) patients proceeded with testing, whereas 74 of 84 (88%) patients did not complete testing. For patients who received in-office genetic testing, 104 of 105 (99%) completed testing. The difference in test completion was statistically significant (P < .001). In addition, genetic testing for out-of-office referrals identified a causative mutation in 5 of 10 (50%) patients, whereas in-office genetic testing identified a causative mutation in 42 of 104 (40.4%) patients. The difference in causative mutation discovery was not statistically significant (P = .18) between the 2 groups.
UNASSIGNED: In-office genetic testing is a novel practice pattern that provides a more consistent and accessible method for IRD genetic diagnosis. Compared with an out-of-office referral for genetic testing, in-office genetic testing offers a similar rate of causative gene mutation identification but a greatly higher rate of test completion, therefore potentially offering a much higher yield for genetic diagnosis of IRDs.

Mitochondria are unique organelles of eukaryotic cells that carry their own multicopy number and circular genome. In most mammals, including humans and mice, the size of the chromosome is ~16,000 base pairs and unlike nuclear DNA, mitochondrial DNA (mtDNA) is not densely compacted. This results in mtDNA to be highly accessible for enzymes such as the Tn5 transposase, commonly used for accessible chromatin profiling of nuclear chromatinized DNA. Here, we describe a method for the concomitant sequencing of mtDNA and accessible chromatin in thousands of individual cells via the mitochondrial single-cell assay for transposase accessible chromatin by sequencing (mtscATAC-seq). Our approach extends the utility of existing scATAC-seq products and protocols as we (Nam et al, Nat Rev Genet 22:3-18, 2021) fix cells using formaldehyde to retain mitochondria and its mtDNA within its originating cell, (Buenrostro et al, Nat Methods 10:1213-1218, 2013) modify lysis conditions to permeabilize cells and mitochondria, and (Corces et al, Nat Methods 14:959-962, 2017) optimize bioinformatic processing protocols to collectively increase mitochondrial genome coverage for downstream analysis. Here, we discuss the essentials for the experimental and computational methodologies to generate and analyze thousands of multiomic profiles of single cells over the course of a few days, enabling the profiling of accessible chromatin and mtDNA genotypes to reconstruct clonal relationships and studies of mitochondrial genetics and disease.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by motile ciliary dysfunction and impaired ultrastructure. Despite numerous studies, the genetic basis for about 30% of PCD cases remains to be elucidated. Here, we present the identification and functional analysis of two novel mutations in the gene encoding coiled-coil domain-containing protein 40 (CCDC40), which are found in a familial case of PCD. These novel CCDC40 mutations, NM_017950.4: c.2236-2delA and c.2042_2046delTCACA, NP_060420.2: p.(Ile681fs), were identified by whole-exome sequencing (WES). Sanger sequencing was then performed to confirm the WES results and determine the CCDC40 gene sequences of the proband\'s parents. The c.2042_2046delTCACA mutation disrupts the reading frame of the protein and is therefore predicted to produce a non-functional protein. Using a minigene assay with the pcDNA3.1(+) plasmid, we further investigated the potential pathogenic effects of the c.2236-2delA mutation and found that this mutation leads to formation of a truncated protein via splicing disruption. Thus, in summary, we identified two mutations of the CCDC40 gene that can be considered pathogenic compound heterozygous mutations in a case of familial PCD, thereby expanding the known mutational spectrum of the CCDC40 gene in this disease.

Approximately 10% of cancers have a hereditary predisposition. However, no genetic diagnosis is available in 60%-80% of familial cancers. In some of these families, immune dysregulation-mediated disease is frequent. The immune system plays a critical role in identifying and eliminating tumors; thus, dysregulation of the immune system can increase the risk of developing cancer. This review focuses on some of the genes involved in immune dysregulation the promote the risk for cancer. Genetic counseling for patients with cancer currently focuses on known genes that raise the risk of cancer. In missing hereditary familial cases, the history family of immune dysregulation should be recorded, and genes related to the immune system should be analyzed in relevant families. On the other hand, patients with immune disorders diagnosed with a pathogenic mutation in an immune regulatory gene may have an increased risk of cancer. Therefore, those patients need to be under surveillance for cancer. Gene panel and exome sequencing are currently standard methods for genetic diagnosis, providing an excellent opportunity to jointly test cancer and immune genes.

Diabetic retinopathy (DR) is a common complication and the leading cause of blindness in patients with type 2 diabetes. DR has been shown to be closely correlated with blood glucose levels and the duration of diabetes. However, the onset and progression of DR also display clinical heterogeneity. We applied whole-exome sequencing and RNA-seq approaches to study the gene mutation and transcription profiles in three groups of diabetic patients with extreme clinical phenotypes in DR onset, timing, and disease progression, aiming to identify genetic variants that may play roles in the pathogenesis of DR. We identified 23 putatively pathogenic genes, and ingenuity pathway analysis of these mutated genes reveals their functional association with glucose metabolism, diabetic complications, neural system activity, and dysregulated immune responses. In addition, ten potentially protective genes were also proposed. These findings shed light on the mechanisms underlying the pathogenesis of DR and may provide potential targets for developing new strategies to combat DR.