Relative Reproduction Number of SARS-CoV-2 Omicron (B.1.1.529) Compared with Delta Variant in South Africa

The world identified the rapidly increasing incidence of the causative variant of SARS-CoV-2 Pangolin B [...]

[CASE REPORT] Homozygous N-terminal missense variant in PLEKHG5 associated with intermediate CMT: a case report

Mutations in PLEKHG5, a pleckstrin homology domain containing member of the GEF family, are associated with distal spinal muscular atrophy and intermediate Charcot-Marie-Tooth disease. Here, we describe an isolated case with distal intermediate neuropathy with scapular winging. By whole exome sequencing, we identified the homozygous PLEKHG5 Arg97Gln missense mutation, located in the N-terminal region of the protein. This mutation resides between a zinc-finger motif and a RBD domain, involved in binding rnd3, a RhoA effector protein. We conclude that based on the characteristic phenotype presented by the patient and the supportive genetic findings, the PLEKHG5 mutation is the causative variant.

The PTRHD1 Mutation in Intellectual Disability

Background: Intellectual disability (ID) is a heterogonous disorder with complex etiology. The frequency of autosomal recessive inheritance defects was elevated in a consanguineous family. Methods: In this study, high-throughput DNA sequencing was performed in an Iranian consanguineous family with two affected individuals to find potential causative variants. Whole-exome sequencing was carried out on the proband and Sanger sequencing was implemented for validation of the likely causative variant in the family members. Results: A novel homozygous missense mutation (p.Arg122Trp) was detected in the PTRHD1 gene. Conclusion: PTRHD1 has been recently introduced as a candidate ID and Parkinsonism causing gene. Our findings are in agreement with the clinical spectrum of PTRHD1 mutations; however, our affected individuals suffer from ID manifestations.

Evidence for and localization of proposed causative variants in cattle and pig genomes

Background This paper reviews the localization of published potential causative variants in contemporary pig and cattle reference genomes, and the evidence for their causality. In spite of the difficulties inherent to the identification of causative variants from genetic mapping and genome-wide association studies, researchers in animal genetics have proposed putative causative variants for several traits relevant to livestock breeding. Results For this review, we read the literature that supports potential causative variants in 13 genes (ABCG2, DGAT1, GHR, IGF2, MC4R, MSTN, NR6A1, PHGK1, PRKAG3, PLRL, RYR1, SYNGR2 and VRTN) in cattle and pigs, and localized them in contemporary reference genomes. We review the evidence for their causality, by aiming to separate the evidence for the locus, the proposed causative gene and the proposed causative variant, and report the bioinformatic searches and tactics needed to localize the sequence variants in the cattle or pig genome. Conclusions Taken together, there is usually good evidence for the association at the locus level, some evidence for a specific causative gene at eight of the loci, and some experimental evidence for a specific causative variant at six of the loci. We recommend that researchers who report new potential causative variants use referenced coordinate systems, show local sequence context, and submit variants to repositories.

Familial Hypomagnesemia with Hypercalciuria, Nephrocalcinosis, and Bilateral Chorioretinal Atrophy in a Patient with Homozygous p.G75S Variant in CLDN19

Introduction Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare disorder caused by perturbation in renal reabsorption of magnesium and calcium. Biallelic pathogenic variants either in gene CLDN16 or CLDN19 are responsible for molecular defects. Most patients with CLDN19 variants have been associated with ocular involvements (FHHNCOI). Patient and Methods We had a pediatric patient with hypercalciuric hypomagnesemia and bilateral chorioretinal atrophy. Metabolic profiling and radiology examinations were performed, in addition to whole exome sequencing (WES) used for detection of the causative variant. Results Analysis of WES revealed a homozygous c.223G > A (p.G75S) variant in CLDN19. MutationTaster and Combined Annotation-Dependent Depletion support its deleterious effect and SHERLOC's criteria put it in pathogenic category. This variant is previously reported in compound heterozygous state with other known pathogenic variant. As far as we know, it is the first report of this variant in homozygous state. Conclusion The variant found in our patient is pathogenic and compatible with FHHNCOI characteristics. WES is an advantageous tool in molecular diagnosis and finding genetic pathology of this disease. In line with other reports, ocular abnormalities are variable in patients with CLDN19 mutations, and chronic kidney disease and retinal damages must be considered in this group.

Molecular Investigation of Iranian Patients Suspected to Hereditary Spherocytosis

Introduction: Hereditary spherocytosis is a heterogeneous disorder with mild to moderate anemia. The aim of this study was to evaluate the inherited spherocytosis gene mutations in patients with RBC cytoplasmic disorders in Iranian population. Materials and Methods: In this study, Whole Exome Sequencing (WES) was performed for patients suspected to hereditary spherocytosis and their relatives. Results: Sequence analysis of the probands and their parents identified variations in ANK1 gene (NM_001142446.1:c.127-2A>G), SPTB (c. 14delC, p.Thr5LysfsTer41), SPTA1 (c.466C>T), SLC4A1 (c.2494C>T) and SLC25A38 gene (c.683G>T, NP_060345.2:p.Gly228Val that could be related to the patients clinical manifestation. Conclusion: Findings are in line with the appropriate diagnostic yield of WES in determining the causative variant especially in those disorders that many genes are involved like anemia. This is the first report of a cohort of Iranian patients with anemia suspected to that were investigated using WES technology. Further studies are needed to investigate the distribution of gene mutations in patients with RBC membrane disorders in Iran

Causative variant profile of collagen VI-related dystrophy in Japan

Background Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities. Methods We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis. Results Of a total of 130 families with 1–5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants. Conclusions We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment.

Atypical Pantothenate Kinase-Associated Neurodegeneration with Variable Phenotypes in an Egyptian Family

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare hereditary neurodegenerative disease characterized by an accumulation of iron within the brain. In the present report, we describe a family with 4 affected siblings presenting with variable clinical manifestations, e.g., parkinsonian features, dystonia and slow disease progression over 5 years. Exome sequencing revealed a causative variant in the pantothenate kinase 2 gene (PANK2). Variant NM_024960.6:c.710C > T was homozygous in all affected subjects. Our report describes the first genetically confirmed cases of PKAN in the Egyptian population. Studying genetics of neurodegenerative diseases in different ethnicities is very important for determining clinical phenotypes and understanding pathomechanisms of these diseases.

Australia and New Zealand renal gene panel testing in routine clinical practice of 542 families

Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.

A COL7A1 Variant in a Litter of Neonatal Basset Hounds with Dystrophic Epidermolysis Bullosa

We investigated three neonatal Basset Hound littermates with lesions consistent with epidermolysis bullosa (EB), a group of genetic blistering diseases. A clinically normal bitch was bred to her grandfather by artificial insemination. Out of a litter of seven puppies, two affected puppies died and one was euthanized, with these puppies being submitted for diagnostic necropsy. All had multiple bullae and ulcers involving the nasal planum and paw pads, as well as sloughing claws; one puppy also had oral and esophageal ulcers. The complete genome of one affected puppy was sequenced, and 37 known EB candidate genes were assessed. We found a candidate causative variant in COL7A1, which encodes the collagen VII alpha 1 chain. The variant is a complex rearrangement involving duplication of a 107 bp region harboring a frameshift deletion of 7 bp. The variant is predicted to truncate more than 75% of the open reading frame, p.(Val677Serfs*11). Targeted genotyping of this duplication confirmed that all three affected puppies were homozygous for the duplication, whereas 12 unaffected Basset Hounds did not carry the duplication. This variant was also not seen in the genomes of more than 600 dogs of other breeds. COL7A1 variants have been identified in humans and dogs with dystrophic epidermolysis bullosa (DEB). The identified COL7A1 variant therefore most likely represents the causative variant and allows the refinement of the preliminary EB diagnosis to DEB.