Splicing mutation in TAZ gene leading to exon skipping and Barth syndrome

Barth syndrome is a monogenic X-linked disorder characterized by cardiomyopathy, skeletal myopathy and neutropenia. It is caused by deficiency of cardiolipin and associated with mutations in the tafazzin gene (TAZ). A 3 years old boy with dilated cardiomyopathy, neutropenia and growth retardation was investigated. Genetic screening found a new variant in the junction of intron 2 and exon 3 of the TAZ gene - c.239-1_239delinsTT. Functional analysis of the variant revealed the aberrant splicing of exon 3 leading to its complete excision from mature mRNA and frameshift at the beginning of tafazzin. Variant c.239-1_239delinsTT can be classified as pathogenic based on splicing alteration and typical clinical phenotype observed in TAZ mutation carriers

New deletion in LAMP2 causing familial Danon disease:effect of X-chromosome inactivation

Danon disease (DD), a rare X-linked genetic illness with a poor prognosis, is caused by a mutation in the lysosome-associated membrane protein 2 gene (LAMP2). Three main clinical features of this pathology are cardiomyopathy, skeletal myopathy, and mental retardation. Most Danon disease mutations create premature stop codons resulting in the decrease or absence of LAMP2 protein. The present case reports the frameshift variant c.190_191delАС in the LAMP2 in the family with sudden cardiac death history and three members with cardiomyopathy. The presenting phenotype in a female proband with c.190_191delАС was isolated dilated cardiomyopathy in her thirties whereas in two males, DD presented as hypertrophic cardiomyopathy and mild skeletal myopathy since childhood. To examine the contribution of X-inactivation to cardiomyopathy onset we estimated the X-inactivation status in the heart tissue of the affected female. We observed the random pattern (66:34) with the proportion of cardiomyocytes expressing healthy LAMP2 allele reduced to 34%. Deletion c.190_191delАС has led to a complete loss of function LAMP2 due to a single copy of this gene in males. In a woman, cardiomyopathy developed because of both the LAMP2 mutation and a decrease in the expression of a healthy allele in the heart. Based on the strong association of truncating LAMP2 mutations with DD and phenotypes in affected members, the variant c.190_191delАС was classified as pathogenic

Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool

Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups – a profile which is very similar to the two other eastern European populations – Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively

Optimised, Broad NGS Panel for Inherited Eye Diseases to Diagnose 1000 Patients in Poland

Advances in gene therapy and genome editing give hope that new treatments will soon be available for inherited eye diseases that together affect a significant proportion of the adult population. New solutions are needed to make genetic diagnosis fast and affordable. This is the first study of such a large group of patients with inherited retinal dystrophies (IRD) and inherited optic neuropathies (ION) in the Polish population. It is based on four years of diagnostic analysis using a broad, targeted NGS approach. The results include the most common pathogenic variants, as well as 91 novel causative variants, including frameshifts in the cumbersome RPGR ORF15 region. The high frequency of the ABCA4 complex haplotype p.(Leu541Pro;Ala1038Val) was confirmed. Additionally, a deletion of exons 22–24 in USH2A, probably specific to the Polish population, was uncovered as the most frequent copy number variation. The diagnostic yield of the broad NGS panel reached 64.3% and is comparable to the results reported for genetic studies of IRD and ION performed for other populations with more extensive WES or WGS methods. A combined approach to identify genetic causes of all known diseases manifesting in the posterior eye segment appears to be the optimal choice given the currently available treatment options and advanced clinical trials

Maximum Parsimony tree (based on MJ network) of NRY haplogroup I2a(P37) calculated from <i>seven</i> Y-STRs.

<p>Balkan populations include Bosnians, Croatians and Slovenians. Altogether 347 individuals are analyzed, the sample size of each population and the set of Y-STRs used for calculations are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499.s014" target="_blank">Table S9</a>.</p

Maximum parsimony tree of mtDNA haplogroup N1a3.

<p>The tree includes 20 novel complete sequences (marked with an asterisk and underlined accession numbers) and eight previously published <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499-Fernandes1" target="_blank">[42]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499-Schnberg1" target="_blank">[50(and references therein)]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499-Behar1" target="_blank">[51]</a>. Mutations relative to the RSRS <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499-Behar1" target="_blank">[51]</a> are indicated on the branches; transversions are specified with a lower case letter; Y and R stand for heteroplasmy; underlining indicates positions experiencing recurrent mutations within the tree while exclamation marks refer to one (!) or two (!!) back mutations relative to the RSRS. Coalescence age estimates for N1a3 and N1a3a obtained by employing the complete genome and synonymous (ρ) clocks, indicated by # and @, respectively, are also shown.</p

Maximum parsimony tree of mtDNA haplogroup N3.

<p>The tree includes 13 novel (marked with an asterisk and underlined accession numbers) and three previously published <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499-Schnberg1" target="_blank">[50]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499-Behar1" target="_blank">[51]</a> complete sequences. Mutations relative to the RSRS <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499-Behar1" target="_blank">[51]</a> are shown on the branches; transversions are specified with a lower case letter; underlining indicates positions which experienced recurrent mutations within the tree, while the exclamation mark (!) refers to one back mutation relative to the RSRS. Rho coalescence time estimates and their confidence intervals for haplogroup N3 and its major sub-branch N3a obtained from the complete genome clock are also shown.</p

PC plot based on NRY haplogroup frequencies among eastern Europeans and Balkan populations.

<p>The contribution of each haplogroup to the first and the second PCs are shown in gray. Population abbreviations are as follows: BeN, BeW, BeC, BeWP, BeEP, BeE – Belarusians from North, West, Central, West Polesie, East Polesie and East sub-regions, respectively, filled red circle denotes the total Belarusian population; RuS, RuC, RuN – Russians from southern, central and northern regions, respectively; Finns K – Finns from Karelia. K*(x N,P) refers to samples with M9, M20, M70 derived alleles and 92R7, M214 ancestral alleles; P*(xR) refers to samples with 92R7, M242 derived alleles and M207 ancestral allele; F*(xI,J,K) refers to samples with M89 derived allele and M9, M201, M170, 12f2 ancestral alleles; C(xF)DE refers to samples with Yap and M130 derived and M89 ancestral alleles. Frequencies of NRY haplogroups and references are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499.s008" target="_blank">Table S3</a>.</p

Phylogeny of mtDNA haplogroups and their relative frequencies in Belarusians.

<p>The tree is rooted relative to the RSRS according to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499-Behar1" target="_blank">[51]</a>. Belarusian sub-populations are designated as BeE – East, BeWP – West Polesie, BeEP – East Polesie, BeN – North, BeC – Centre, BeW – West. Sample sizes and absolute frequencies are also given.</p

Geographic position of Belarus within Europe.

<p>Map of Belarus demonstrating the six geographic sub-regions studied is shown on the right. Numbers 1–19 correspond to the location of sampling points (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066499#pone.0066499.s006" target="_blank">Table S1</a>). Lit – Lithuania, Lat – Latvia, Est – Estonia.</p