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Gerstmann-Sträussler disease (GSD) is a very rare autosomal dominant late-onset neurodegenerative disorder related to prion protein gene PRNP . Mutation p.Pro102Leu produces about 80% of cases, which are often named GSD-102. DNA testing provides exact diagnosis. In the presented Russian family there were 3 patients: a female index case, age 32 years, her brother, age 37 years (age of onset in both is 27 years) and their deceased father (onset in 35 years, death in 44 years). GSD was not suspected until whole exome sequencing in the female detected PRNP mutation p.Pro102Leu confirmed in her and in the brother by Sanger sequencing. Atypical features of the case are: early onset in siblings, absence of mental and behavioral problems in the female and in the father and mild disturbances in the brother; epilepsy in the brother; atypical onset with transient signs in the brother. Other intrafamilial differences are prevailing spastic paraparesis in the female in contrast to predominant ataxia in the brother and dysarthria absence in the female. The case illustrates GSD-102 variability, complicating clinical diagnostics.

Key Message: We present a comprehensive survey of cytogenetic and genomic diversity of the GGA t A t genepool of wheat, thereby unlocking these plant genetic resources for wheat improvement. Wheat yields are stagnating around the world and new sources of genes for resistance or tolerances to abiotic traits are required. In this context, the tetraploid wheat wild relatives are among the key candidates for wheat improvement. Despite its potential huge value for wheat breeding, the tetraploid GGA t A t genepool is largely neglected. Understanding the population structure, native distribution range, intraspecific variation of the entire tetraploid GGA t A t genepool and its domestication history would further its use for wheat improvement. The paper provides the first comprehensive survey of genomic and cytogenetic diversity sampling the full breadth and depth of the tetraploid GGA t A t genepool. According to the results obtained, the extant GGA t A t genepool consists of three distinct lineages. We provide detailed insights into the cytogenetic composition of GGA t A t wheats, revealed group- and population-specific markers and show that chromosomal rearrangements play an important role in intraspecific diversity of T. araraticum. The origin and domestication history of the GGA t A t lineages is discussed in the context of state-of-the-art archaeobotanical finds. We shed new light on the complex evolutionary history of the GGA t A t wheat genepool and provide the basis for an increased use of the GGA t A t wheat genepool for wheat improvement. The findings have implications for our understanding of the origins of agriculture in southwest Asia., (© 2021. The Author(s).)

Congenital autosomal recessive cataract with unknown genetic etiology is one of the most common Mendelian diseases among the Turkic-speaking Yakut population (Eastern Siberia, Russia). To identify the genetic cause of congenital cataract spread in this population, we performed whole-exome sequencing (Illumina NextSeq 500) in one Yakut family with three affected siblings whose parents had preserved vision. We have revealed the novel homozygous c.1621C>T transition leading to premature stop codon p.(Gln541*) in exon 8 of the FYCO1 gene (NM_024513.4). Subsequent screening of c.1621C>T p.(Gln541*) revealed this variant in a homozygous state in 25 out of 29 Yakut families with congenital cataract (86%). Among 424 healthy individuals from seven populations of Eastern Siberia (Russians, Yakuts, Evenks, Evens, Dolgans, Chukchi, and Yukaghirs), the highest carrier frequency of c.1621C>T p.(Gln541*) was found in the Yakut population (7.9%). DNA samples of 25 homozygous for c.1621C>T p.(Gln541*) patients with congenital cataract and 114 unaffected unrelated individuals without this variant were used for a haplotype analysis based on the genotyping of six STR markers (D3S3512, D3S3685, D3S3582, D3S3561, D3S1289, and D3S3698). The structure of the identified haplotypes indicates a common origin for all of the studied mutant chromosomes bearing c.1621C>T p.(Gln541*). The age of the с.1621C>T p.(Gln541*) founder haplotype was estimated to be approximately 260 ± 65 years (10 generations). These findings characterize Eastern Siberia as the region of the world with the most extensive accumulation of the unique variant c.1621C>T p.(Gln541*) in the FYCO1 gene as a result of the founder effect.

Hereditary nonsyndromic sensorineural hearing loss is a disease in which hearing loss occurs due to damage to the organ of the inner ear, the auditory nerve, or the center in the brain that is responsible for the perception of sound, characterized by wide locus and allelic heterogeneity and different types of inheritance. Given the diversity of population of the Russian Federation, it seems necessary to study the ethnic characteristics of the molecular causes of the disease. The aim is to study the molecular and genetic causes of hereditary sensorineural hearing loss in Chuvash, the fifth largest ethnic group in Russia. DNA samples of 26 patients from 21 unrelated Chuvash families from the Republic of Chuvashia, in whom the diagnosis of hereditary sensorineural hearing loss had been established, were analyzed using a combination of targeted Sanger sequencing, multiplex ligase-dependent probe amplification, and whole exome sequencing. The homozygous variant NM_133261.3( GIPC3 ):c.245A>G (p.Asn82Ser) is the major molecular cause of hereditary sensorineural hearing loss in 23% of Chuvash patients (OMIM #601869). Its frequency was 25% in patients and 1.1% in healthy Chuvash population. Genotyping of the NM_133261.3( GIPC3 ):c.245A>G (p.Asn82Ser) variant in five neighboring populations from the Volga-Ural region (Russian, Udmurt, Mary, Tatar, Bushkir) found no evidence that this variant is common in those populations.

A young boy with multifocal epilepsy with infantile spasms and hypsarrhythmia with minimal organic lesions of brain structures underwent DNA diagnosis using whole-exome sequencing. A heterozygous amino-acid substitution p.L519R in a PHACTR1 gene was identified. PHACTR1 belongs to a protein family of G-actin binding protein phosphatase 1 (PP1) cofactors and was not previously associated with a human disease. The missense single nucleotide variant in the proband was shown to occur de novo in the paternal allele. The mutation was shown in vitro to reduce the affinity of PHACTR1 for G-actin, and to increase its propensity to form complexes with the catalytic subunit of PP1. These properties are associated with altered subcellular localization of PHACTR1 and increased ability to induce cytoskeletal rearrangements. Although the molecular role of the PHACTR1 in neuronal excitability and differentiation remains to be defined, PHACTR1 has been previously shown to be involved in Slack channelopathy pathogenesis, consistent with our findings. We conclude that this activating mutation in PHACTR1 causes a severe type of sporadic multifocal epilepsy in the patient., (© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

A family of five male siblings (three survivors at 48, 53 and 58 years old; two deceased at 8 months old and 2.5 years old) demonstrating significant phenotypic variability ranging from intermediate to the myosclerotic like Bethlem myopathy is presented. Whole-exome sequencing (WES) identified a new homozygous missense mutation chr21:47402679 T > C in the canonical splice donor site of the second intron (c.227 + 2T>C) in the COL6A1 gene. mRNA analysis confirmed skipping of exon 2 encoding 925 amino-acids in 94-95% of resulting transcripts. Three sibs presented with intermediate phenotype of collagen VI-related dystrophies (48, 53 and 2.5 years old) while the fourth sibling (58 years old) was classified as Bethlem myopathy with spine rigidity. The two older siblings with the moderate progressive phenotype (48 and 53 years old) lost their ability to maintain a vertical posture caused by pronounced contractures of large joints, but continued to ambulate throughout life on fully bent legs without auxiliary means of support. Immunofluorescence analysis of dermal fibroblasts demonstrated that no type VI collagen was secreted in any of the siblings' cells, regardless of clinical manifestations severity while fibroblast proliferation and colony formation ability was decreased. The detailed genetic and long term clinical data contribute to broadening the genotypic and phenotypic spectrum of COL6A1 related disease.

Objective: To estimate the proportion and spectrum of infrequent autosomal dominant spastic paraplegias in a group of families with DNA-confirmed diagnosis and to investigate their molecular and clinical characteristics., Material and Methods: Ten families with 6 AD-SPG: SPG6 ( n =1), SPG8 ( n =2), SPG9A ( n =1), SPG12 ( n =1), SPG17 ( n =3), SPG31 ( n =2) were studied using clinical, genealogical, molecular-genetic (massive parallel sequencing, spastic paraplegia panel, whole-exome sequencing, multiplex ligation-dependent amplification, Sanger sequencing) and bioinformatic methods., Results and Conclusion: Nine heterozygous mutations were detected in 6 genes, including the common de novo mutation p.Gly106Arg in NIPA1 (SPG6), the earlier reported mutation p.Val626Phe in WASHC5 (SPG8) in isolated case and the novel p.Val695Ala in WASHC5 (SPG8) in a family with 4 patients, the novel mutation p.Thr301Arg in RTN2 (SPG12) in a family with 2 patients, the novel mutation c.105+4A>G in REEP1 (SPG31) in a family with 4 patients and the reported earlier p.Lys101Lys in REEP1 (SPG31) in a family with 3 patients, the known de novo mutation p.Arg252Gln in ALDH18A1 (SPG9A) in two monozygous twins; the common mutation p.Ser90Leu in BSCL2 (SPG17) in a family with 3 patients and in isolated case, reported mutation p.Leu363Pro in a family with 2 patients. SPG6, SPG8, SPG12 and SPG31 presented 'pure' phenotypes, SPG31 had most benign course. Age of onset varied in SPG31 family and was atypically early in SPG6 case. Patients with SPG9A and SPG17 had 'complicated' paraplegias; amyotrophy of hands typical for SPG17 was absent in a child and in an adolescent from 2 families, but may develop later.

Background: Mutations in CRYAA, which encodes the α-crystallin protein, are associated with a spectrum of congenital cataract-microcornea syndromes., Results: In this study, we performed clinical examination and subsequent genetic analysis in two unrelated sporadic cases of different geographical origins presenting with a complex phenotype of ocular malformation. Both cases manifested bilateral microphthalmia and severe anterior segment dysgenesis, primarily characterized by congenital aphakia, microcornea, and iris hypoplasia/aniridia. NGS-based analysis revealed two novel single nucleotide variants occurring de novo and affecting the translation termination codon of the CRYAA gene, c.520T > C and c.521A > C. Both variants are predicted to elongate the C-terminal protein domain by one-third of the original length., Conclusions: Our report not only expands the mutational spectrum of CRYAA but also identifies the genetic cause of the unusual ocular phenotype described in this report.

Ataxia with oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive, PNKP -related disorder delineated in 2015 in Portugal. We diagnosed AOA4 by next generation sequencing (NGS) followed by Sanger's sequencing in three boys from two unrelated Belarusian families. In both families, one of the heterozygous PNKP mutations was c.1123G>T, common in Portuguese patients; biallelic mutations, c.1270_1283dup14 and c.1029+2T>C, respectively, were novel. These are the first reported AOA4 Slavic cases and the first with a "Portuguese" PNKP mutation outside Portugal. Distinction in two brothers was microcephaly but their disease was not severe in contrast to PNKP -related "microcephaly, seizures, and developmental delay" and reported cases with features of both phenotypes.

The authors present an unique familial case of ataxia-telangiectasia (AT) mimicking autosomal dominant inheritance with different phenotypes in a 3-year-old boy (ataxia and moderate dyskinesia since 1.5 years) and his 31-year-old mother (mild dystonia, predominantly torticollis, since 10 years). Exome sequencing of the boy detected two heterozygous ATM mutations c.1564_1565delGA (p.Glu522fs) and c.6154G>A (p.Glu2052Lys) reported earlier. Sanger sequencing found both mutations in the child, the father was heterozygous for c.1564_1565delGA, the mother for 6154G>A earlier reported in the rare A-T phenotype of 'pure' local dystonia. Exome sequencing of the mother, who considered herself healthy, detected the allelic ATM mutation c.7630-2A>C in intron 51.

Intellectual disability is the most common developmental disorder caused by chromosomal aberrations as well as single-nucleotide variants (SNVs) and small insertions/deletions (indels). Here we report identification of a novel, probably pathogenic mutation in the WHSC1 gene in a patient case with phenotype overlapping the features of Wolf-Hirschhorn syndrome. Deletions involving WHSC1 (Wolf-Hirschhorn syndrome candidate 1 gene) were described earlier in patients with Wolf-Hirschhorn syndrome. However, to our knowledge, single-point mutations in WHSC1 associated with any intellectual deficiency syndromes have not been reported. Using whole exome sequencing, we found a de novo nonsense mutation in WHSC1 (c.3412C>T, p.Arg1138Ter, NM_001042424.2) in patient with syndromic intellectual disability. This finding is challenging regarding a possible causative role of WHSC1 in intellectual disability syndromes, specifically Wolf-Hirschhorn syndrome. From the clinical standpoint, our finding suggests that next-generation sequencing along with chromosome microarray analysis (CMA) might be useful in genetic testing for patients with intellectual disability and dysmorphic features.

Background: Primary microcephaly represents an example of clinically and genetically heterogeneous condition. Here we describe a case of primary microcephaly from the Karachay-Cherkess Republic, which was initially diagnosed with Seckel syndrome., Case Presentation: Clinical exome sequencing of the proband revealed a novel homozygous single nucleotide deletion in ASPM gene, c.1386delC, resulting in preterm termination codon. Population screening reveals allele frequency to be less than 0.005. Mutations in this gene were not previously associated with Seckel syndrome., Conclusions: Our case represents an additional support for the clinical continuum between Seckel Syndrome and primary microcephaly.

Ataxias with oculomotor apraxia (AOA) belong to autosomal recessive ataxias. Their common feature is oculomotor apraxia: inability to coordinate eye movements not due to muscle weakness. Next-generation sequencing (NGS) gives unique opportunities of rare disorders diagnostics and discovering of new forms, including AOA. In 2015, AOA type 4 produced by PNKP mutations was delineated in a group of Portuguese patients. We diagnosed AOA4 in a 9-year-old boy from Byelorussian family. He presented with ataxia since 2 years and deterioration in 8 years, oculomotor apraxia, dystonic hyperkinesia, dysarthria, polyneuropathy, borderline/mildly impaired intelligence, cerebellar atrophy on MRI and moderate hypercholesterolemia. Panel NGS detected two PNKP mutations: c.1123G>T (p.Gly375Trp) common in Portuguese patients, and novel c.1270_1283dupACAAACCCAGACGC (p.Ala429fs). This is one of a few world AOA4 cases and first non-Portuguese case with 'Portuguese' common mutation. The case illustrates NGS diagnostic value, particularly in rare heterogeneous disorders like AOA.

Aim: To determine clinical and genetic characteristics of patients with non-syndromic mental retardation (NMR), type 20 with autosomal dominant type of inheritance (OMIM: 613443)., Material and Methods: Fourteen patients were studied including four patients with mutations in the MEF2C gene revealed by exome sequencing. Three of the four mutations in the gene were found for the first time., Results: Based on a comparative analysis of the clinical manifestations of 4 observed patients and 9 patients with type 20 NMR described in the literature, the authors determined common clinical characteristics of this syndrome. In most cases with delayed psycho-speech development and convulsive syndrome, the patients were expected to have various variants of early epileptic encephalopathies, in which presence of convulsive paroxysms leads to intellectual deficit, while in the case of NMR, the delay in development can be noted long before the onset of seizures., Conclusion: Exome sequencing is the most effective method of NMR diagnosis.

To paper describes a case of paucicellular anaplastic cancer in the presence of tall cell variant papillary thyroid carcinoma. Microscopic examination showed that the differentiated component of the tumor was composed of papillary structures with tall cells, the height of which exceeded 3-4 times the width. Its anaplastic component consisted of fibrous tissue with occasional spindle-shaped cells and focal lymphocytic infiltration to the extent of 70%. The spindle-shaped cells expressed cytokeratins, β-catenin, p53, and vimentin. The tumor cells and lymphocytes showed an association with Epstein-Barr virus. Molecular genetic study of the tumor revealed the following mutations: BRAF p.Val600Glu (p.V600e was), HRAS p.His27His (p.H27H), PIK3CA p.Glu545Lys (p.E545K), TP53 p.Arg248Gln (p.R248Q).

Hypotrichosis is an abnormal condition characterized by decreased hair density and various defects in hair structure and growth patterns. In particular, in woolly hair, hypotrichosis is characterized by a tightly curled structure and abnormal growth. In this study, we present a detailed comparative examination of individuals affected by autosomal-recessive hypotrichosis (ARH), which distinguishes two types of ARH. Earlier, we demonstrated that exon 4 deletion in the lipase H gene caused an ARH (hypotrichosis 7; MIM: 604379) in populations of the Volga-Ural region of Russia. Screening for this mutation in all affected individuals revealed its presence only in the group with the hypotrichosis 7 phenotype. Other patients formed a separate group of woolly hair-associated ARH, with a homozygous missense mutation c.712G>T (p.Val238Leu) in a highly conserved position of type I keratin KRT25 (K25). Haplotype analysis indicated a founder effect. An expression study in the HaCaT cell line demonstrated a deleterious effect of the p.Val238Leu mutation on the formation of keratin intermediate filaments. Hence, we have identified a previously unreported missense mutation in the KRT25 gene causing ARH with woolly hair., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Molecular markers based on retrotransposon insertions are widely used for various applications including phylogenetic analysis. Multiple cases were described where retrotransposon-based markers, namely sequence-specific amplification polymorphism (SSAP), were superior to other marker types in resolving the phylogenetic relationships due to their higher variability and informativeness. However, the patterns of evolutionary relationships revealed by SSAP may be dependent on the underlying retrotransposon activity in different periods of time. Hence, the proper choice of retrotransposon family is essential for obtaining significant results. We compared the phylogenetic trees for a diverse set of diploid A-genome wheat species (Triticum boeoticum, T. urartu and T. monococcum) based on two unrelated retrotransposon families, BARE-1 and Jeli. BARE-1 belongs to Copia class and has a uniform distribution between common wheat (T. aestivum) genomes of different origin (A, B and D), indicating similar activity in the respective diploid genome donors. Gypsy-class family Jeli was found by us to be an A-genome retrotransposon with >70% copies residing in A genome of hexaploid common wheat, suggesting a burst of transposition in the history of A-genome progenitors. The results indicate that a higher Jeli transpositional activity was associated with T. urartu versus T. boeoticum speciation, while BARE-1 produced more polymorphic insertions during subsequent intraspecific diversification; as an outcome, each retrotransposon provides more informative markers at the corresponding level of phylogenetic relationships. We conclude that multiple retroelement families should be analyzed for an image of evolutionary relationships to be solid and comprehensive.

The CAPS (PCR-PDRF) method was used to analyze polymorphism in sequences of unique genes among specimens of 24 pea lines and cultivars. Analysis of each employed molecular-genetic marker was found to reveal three to seven polymorphic sequence variants. Analysis with the use of five selected markers allows the unambiguous identification of any of examined specimens. Thus, the possibility of using CAPS markers for identification and classification of garden pea cultivars has been shown. Possible prospects for this approach and the ways of its further implementation are considered.

The authors' studies on the organization and variation of plant genome with the use of molecular markers are briefly reviewed with special emphasis on random amplified polymorphic DNA (RAPD), inter simple sequence repeat (ISSR), sequence characterized amplified region (SCAR), and cleaved amplified polymorphic sequence (CAPS) markers detected with the use of polymerase chain reaction (PCR). These markers have been demonstrated to be promising for identifying cultivars and determining the purity of genetic strains of pea. Genetic relationships between strains, cultivars, and mutants of pea have been studied. The role of molecular markers in molecular genetic mapping and localizing the genes of commercially important characters of pea has been shown. The possibility of the use of molecular markers for studying somaclonal variation and detecting mutagenic factors in plants during long-term spaceflights is considered. The prospects of using DNA markers for understanding the organization and variability of higher plant genomes are discussed.

Various pea cultivars, lines, and mutants were studied by the RAPD method. Polymorphic fragments characteristic of certain pea genotypes and which can be used for identifying genotypes were detected. Inheritance of some polymorphic RAPD fragments was studied. Mendelian inheritance of these fragments was shown. By analyzing the data obtained in studies of RAPD polymorphism, genetic distances between different pea cultivars, lines, and mutants were calculated and a genealogic dendogram showing a varying extent of differences between RAPD patterns was constructed. Ten new RAPD markers linked to various pea genes were detected. Genetic distances between RAPD markers and genes to which they are linked were calculated, and the respective disposition of RAPD markers on chromosomes was established.

The authors' studies on the organization and variation of plant genome with the use of molecular markers are briefly reviewed with special emphasis on random amplified polymorphic DNA (RAPD), inter simple sequence repeat (ISSR), sequence characterized amplified region (SCAR), and cleaved amplified polymorphic sequence (CAPS) markers detected with the use of polymerase chain reaction (PCR). These markers have been demonstrated to be promising for identifying cultivars and determining the purity of genetic strains of pea. Genetic relationships between strains, cultivars, and mutants of pea have been studied. The role of molecular markers in molecular genetic mapping and localizing the genes of commercially important characters of pea has been shown. The possibility of the use of molecular markers for studying somaclonal variation and detecting mutagenic factors in plants during long-term spaceflights is considered. The prospects of using DNA markers for understanding the organization and variability of higher plant genomes are discussed., (© MAIK “Nauka/Interperiodica” 2005.)

Chlorophyll mutant Chi115 was induced by ethylmethane sulfonate (EMS) treatment of seeds of genotype Torsdag in Moscow State University and is characterized by lighter plant color. The monogenic nature of the mutant was determined by analyzing the F2 population from a cross between two P. sativum genotypes, WL1238 and Chi115. To establish a local map around the chi115 gene, the RAPD and ISSR techniques were used with 45 RAPD and 10 ISSR primers in combination with bulked segregant analysis (BSA). Linkage of 12 RAPDs and 2 ISSRs to the chi115 locus was observed in analysis of F2 single plants. Two RAPD markers that were closely associated with the chi115 gene were converted into the sequence characterized amplified region (SCAR) markers. By lowering the LOD score to 2, the linkage group containing the chi115 gene could be linked to the b gene (color of the flower) on linkage group III. Nevertheless, to prove the result obtained, three CAPS markers Sodmt, TubA1, and Rb were chosen on linkage group III. The results of linkage analysis showed that these CAPS markers were located within the linkage group including the chi115 gene.