Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification

Primary familial brain calcification (PFBC) is a progressive neurological disorder manifesting as bilateral brain calcifications in CT scan with symptoms as parkinsonism, dystonia, ataxia, psychiatric symptoms, etc. Recently, pathogenic variants in MYORG have been linked to autosomal recessive PFBC. This study aims to elucidate the mutational and clinical spectrum of MYORG mutations in a large cohort of Chinese PFBC patients with possible autosomal recessive or absent family history. Mutational analyses of MYORG were performed by Sanger sequencing in a cohort of 245 PFBC patients including 21 subjects from 10 families compatible with a possibly autosomal-recessive trait and 224 apparently sporadic cases. In-depth phenotyping and neuroimaging features were investigated in all patients with novel MYORG variants. Two nonsense variants (c.442C > T, p. Q148*; c.972C > A, p. Y324*) and two missense variants (c.1969G>C, p. G657R; c.2033C > G, p. P678R) of MYORG were identified in four sporadic PFBC patients, respectively. These four novel variants were absent in gnomAD, and their amino acid were highly conserved, suggesting these variants have a pathogenic impact. Patients with MYORG variants tend to display a homogeneous clinical spectrum, showing extensive brain calcification and parkinsonism, dysarthria, ataxia, or vertigo. Our findings supported the pathogenic role of MYORG variants in PFBC and identified two pathogenic variants (c.442C > T, c.972C > A), one likely pathogenic variant (c.2033C > G), and one variant of uncertain significance (c.1969G>C), further expanding the genetic and phenotypic spectrum of PFBC-MYORG.

PSI-B-27 Association of multiple SNP in the LRP4 gene with features of the cattle elemental status

Bovine syndactyly is an autosomal monogenic recessive trait associated with multiple mutations in the LRP4 gene encoding low-density lipoprotein receptor-related protein 4. This protein is a specific facilitator of sclerostin-mediated inhibition of both Wnt1/ β-catenin signaling and osteocyte-secreted bone formation. It is assumed that sclerostin induces a decrease in extracellular pH and promotes the release of calcium ions from mineralized substrates. Therefore, mutations in the LRP4 gene might be associated with changes in the elemental status. The aim of this research was to evaluate the elemental composition of serum in cattle carrying multiple SNP in the LRP4 gene (16 trial animals) compared to animals without such mutations (62 control animals). DNA samples from 78 Black Pied cattle were sequenced with a TruSeq Bovine Parentage Sequencing Panel (Illumina, USA) on a MiSeq Illumina platform following by SNP analysis. The elemental composition of the serum was determined using ICP-AES and ICP-MS. The levels of Ca and P, crucial bone elements, were higher in trial cattle than in control group by 12.9% (P = 0.004) and 22.5% (P = 0.008), respectively. The level of V affecting the uniform distribution of calcium salts in bones, was higher in trial group than in control one by 34.5% (P = 0.001). The concentrations of Mn and Mg were higher in trial group than in control one by 23.6% (P = 0.026) and 10.0% (P = 0.044), respectively. The Sr level in trial cattle was higher by 18.8% (P = 0.04) that may indicate the rickets-like state. A similar trend was observed for toxic metals As and Li. This study demonstrates the association of the LRP4 multiple SNP and the changes in cattle elemental status. Moreover, such heterozygous animals have a higher risk of mineral metabolism disorders. This research was supported by The Ministry of Science and Higher Education of the Russian Federation (Project No. 0526-2019-0001).

Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene

Objective: To investigate the clinical course and genetic etiology of familial temperature-sensitive auditory neuropathy (TSAN), which is a very rare subtype of auditory neuropathy (AN) that involves an elevation of hearing thresholds due to an increase in the core body temperature, and to evaluate the genotype–phenotype correlations in a family with TSAN.Methods: Six members of a non-consanguineous Chinese family, including four siblings complaining of communication difficulties when febrile, were enrolled in this study. The clinical and audiological profiles of the four siblings were fully evaluated during both febrile and afebrile episodes, and the genetic etiology of hearing loss (HL) was explored using next-generation sequencing (NGS) technology. Their parents, who had no complaints of fluctuating HL due to body temperature variation, were enrolled for the genetics portion only.Results: Audiological tests during the patients’ febrile episodes met the classical diagnostic criteria for AN, including mild HL, poor speech discrimination, preserved cochlear microphonics (CMs), and absent auditory brainstem responses (ABRs). Importantly, unlike the pattern observed in previously reported cases of TSAN, the ABRs and electrocochleography (ECochG) signals of our patients improved to normal during afebrile periods. Genetic analysis identified a compound heterozygous variant of the OTOF gene (which encodes the otoferlin protein), including one previously reported pathogenic variant, c.5098G > C (p.Glu1700Gln), and one novel variant, c.4882C > A (p.Pro1628Thr). Neither of the identified variants affected the C2 domains related to the main function of otoferlin. Both variants faithfully cosegregated with TSAN within the pedigree, suggesting that OTOF is the causative gene of the autosomal recessive trait segregation in this family.Conclusion: The presence of CMs with absent (or markedly abnormal) ABRs is a reliable criterion for diagnosing AN. The severity of the phenotype caused by dysfunctional neurotransmitter release in TSAN may reflect variants that alter the C2 domains of otoferlin. The observations from this study enrich the current understanding of the phenotype and genotype of TSAN and may lay a foundation for further research on its pathogenesis.

A frameshift insertion in FA2H causes a recessively inherited form of ichthyosis congenita in Chianina cattle

The aim of this study was to characterize the phenotype and to identify the genetic etiology of a syndromic form of ichthyosis congenita (IC) observed in Italian Chianina cattle and to estimate the prevalence of the deleterious allele in the population. Sporadic occurrence of different forms of ichthyosis including IC have been previously reported in cattle. However, so far, no causative genetic variant has been found for bovine IC. Nine affected cattle presenting congenital xerosis, hyperkeratosis and scaling of the skin as well as urolithiasis and cystitis associated with retarded growth were examined. Skin histopathology revealed a severe, diffuse orthokeratotic hyperkeratosis with mild to moderate epidermal hyperplasia. The pedigree records indicated a monogenic recessive trait. Homozygosity mapping and whole-genome sequencing allowed the identification of a homozygous frameshift 1 bp insertion in the FA2H gene (c.9dupC; p.Ala4ArgfsTer142) located in a 1.92 Mb shared identical-by-descent region on chromosome 18 present in all cases, while the parents were heterozygous as expected for obligate carriers. These findings enable the selection against this sub-lethal allele showing an estimated frequency of ~ 7.5% in Chianina top sires. A sporadic incidence of mild clinical signs in the skin of heterozygous carriers was observed. So far, pathogenic variants affecting the encoded fatty acid 2-hydroxylase catalyzing the synthesis of 2-hydroxysphingolipids have been associated with myelin disorders. In conclusion, this study represents the first report of an FA2H-related autosomal recessive inherited skin disorder in a mammalian species and adds FA2H to the list of candidate genes for ichthyosis in humans and animals. Furthermore, this study provides a DNA-based diagnostic test that enables selection against the identified pathogenic variant in the Chianina cattle population. However, functional studies are needed to better understand the expression of FA2H in IC-affected Chianina cattle.

Inheritance of Black Rot Resistance and Development of Molecular Marker Linked to Xcc Races 6 and 7 Resistance in Cabbage

Black rot, caused by Xanthomonas campestris pv. campestris (Xcc), produces V-shaped chlorotic lesions on the leaves of cabbage (Brassica oleracea var. capitata L.), causing darkened veins and drastically reducing yield and quality. Of the 11 Xcc races identified, races 1, 4, and 6 are predominant globally. In the present study, we aimed to develop a molecular marker linked to black rot resistance against Xcc races 6 and 7. Crossed between black rot-resistant (‘SCNU-C-3470’) and -susceptible (‘SCNU-C-3328’) lines obtained 186 F2 plants. Resistance to Xcc race 6 segregated in a 3:1 (susceptible:resistant) ratio in the F2 population, which is consistent with a monogenic recessive trait. Nucleotide-binding site (NBS) leucine rich repeat (LRR)-encoding resistance (R) genes play a crucial role in plant defenses to various pathogens. The candidate R gene (Bol031422) located on chromosome C08, previously reported by our research group, was cloned and sequenced in resistant and susceptible cabbage lines. The R gene Bol031422 consisted of a single exon with a 3 bp insertion/deletions (InDels), a 292 bp polymorphism (an insertion in the exon of the resistant line relative to the susceptible line) and several single nucleotide polymorphisms (SNPs). Here, we developed the InDel marker BR6-InDel to assess linkage between variation at Bol031422 and resistance to Xcc races 6 and 7. This marker will help cabbage breeders develop cabbage cultivars resistant to Xcc races 6 and 7.

Papillon-lefevere syndrome-Consanguity as a risk factor in siblings (Case series)

Papillon-Lefevere syndrome is a very rare autosomal recessive trait characterized by palmoplantar hyperkeratosis and severe generalized early-onset periodontitis leading to premature loss of primary and permanent dentitions. Various etiopathogenesis factors are associated with syndrome. The palmoplantar keratoderma typically has its onset between the ages of 1 and 4 years and severe periodontitis starts at age of 3-4 years. A dentist plays an important role in early diagnosing and preserving remaining teeth in oral cavity. This case series describes three cases of PLS in siblings with consanguineously married parents. All siblings in the family were affected which makes this a rare case.

Chondroectodermal dysplasia (Ellis-van Creveld syndrome)

Ellis-van Creveld syndrome (EVC) is a very rare mesenchymal- ectodermal dysplasia. This was first described in 1940 by Richard W. B. Ellis and Simon van Creveld.This rare condition is inherited as an autosomal recessive trait with variable expression. It is also known as mesoectodermal dysplasia or chondroectodermal dysplasia. The main features of this syndrome are short ribs, polydactyly, growth retardation, and ectodermal and heart defects. It is a rare disease with approximately 150 cases reported worldwide. It was found to be more common among the Amish. But sporadic cases have been reported from all over the world including India. The generalized dysplasia of endochondral ossification is because of in a novel gene on chromosome 4p16. Mutations of the EVC1 and EVC2 genes, located in head to head configuration on chromosome 4p16 have been identified as a causative factor

A Sri Lankan girl with a new genetic variant in the PKLR gene causing pyruvate kinase deficiency: a case report

Background Erythrocyte pyruvate kinase is expressed under the control of the PKLR gene located on chromosome 1q21. Pyruvate kinase catalyzes the final steps of the glycolytic pathway and creates 50% of the red cell total adenosine triphosphate. Pyruvate kinase deficiency is the commonest glycolytic defect causing congenital non-spherocytic hemolytic anemia inherited in an autosomal recessive trait in which homozygotes and compound heterozygotes are common. Over 200 mutations have been described in patients with pyruvate kinase deficiency. This case report identifies a new pathogenic variant in PKLR gene detected in a patient with severe pyruvate kinase deficiency. Case presentation A Sri Lankan Sinhalese girl who developed neonatal anemia and jaundice within 24 hours of birth with mild hepatomegaly. She was from a nonconsanguineous marriage and had two siblings who had no hematological disorders. She had repeated admissions due to similar illnesses and at the age of 8 years was found to have pyruvate kinase deficiency associated with a novel homozygous pathogenic variant c.507+1delG in the PKLR gene. Conclusions A novel genetic variant in PKLR gene, consistent with pyruvate kinase deficiency, was detected in a Sri Lankan girl. This genetic variant may be specific to the Asian population and requires further studies.

The First Korean Case of SLC12A3 Aberrant Skipping of Two Exons Detected by RNA Splicing Analysis

Gitelman syndrome is a salt-losing tubular disorder that is transmitted as an autosomal recessive trait. Variants in the <i>SLC12A3</i> gene are found in the majority of Gitelman syndrome patients. A 26-year-old woman visited the genetic counseling clinic. Her fiancé was a known Gitelman syndrome patient who was previously diagnosed with 2 pathogenic variants in <i>SLC12A3</i>. In advance of marriage and future family planning, she wanted to perform genetic testing of <i>SLC12A3</i>. A silent exonic variant c.1050G&#x3e;A was found, and multiple splice site in silico algorithms predicted this variant to have potential alteration of splicing. This variant was classified as “variant of uncertain significance,” and RNA splicing analysis was additionally performed. RNA splicing analysis showed aberrant splicing of exon 7–8 skipping. The result points out the potential pathogenicity of this variant, which should be considered a candidate of variant reclassification in the future. We highly recommend the performance of additional RNA splicing analysis, especially for silent variants predicted to have potential alteration of splicing.

Inheritance of evolved thiocarbamate resistance in Rigid Ryegrass (Lolium rigidum) populations from Australia

Populations of rigid ryegrass (Lolium rigidum Gaudin) from southern Australia have evolved resistance to the thiocarbamate herbicide prosulfocarb. The inheritance of prosulfocarb resistance was explored by crossing R and S individuals. In all families within each cross, except 16.2, the response of the F1 were intermediate between the parents, suggesting that resistance is inherited as a single, partially dominant trait. For 16.2, the response of the F1 was more similar to the susceptible parent, suggesting resistance may be a recessive trait in this population. Segregation at the discriminating dose of 1200 g a.i. ha−1 prosulfocarb in populations 375-14 fitted the ratio (15:1) consistent with two independent dominant alleles; 198-15 fitted a ratio (13:3) for two independent alleles, one dominant and one recessive; and EP162 fitted a ratio (9:7) for two additive dominant alleles. In contrast segregation of population 16.2 fitted a (7:9) ratio consistent with two independent recessive alleles contributing to prosulfocarb resistance. Four different patterns of resistance to prosulfocarb were identified in different resistant populations, with inheritance as a dominant allele, dominant and recessive, additive dominant and as an independent recessive allele. This suggests there are several different mechanisms of prosulfocarb resistance present in L. rigidum.