Jūratė Kasnauskienė

Genetic Structure of Europeans: A View from the North–East

Using principal component (PC) analysis, we studied the genetic constitution of 3,112 individuals from Europe as portrayed by more than 270,000 single nucleotide polymorphisms (SNPs) genotyped with the Illumina Infinium platform. In cohorts where the sample size was >100, one hundred randomly chosen samples were used for analysis to minimize the sample size effect, resulting in a total of 1,564 samples. This analysis revealed that the genetic structure of the European population correlates closely with geography. The first two PCs highlight the genetic diversity corresponding to the northwest to southeast gradient and position the populations according to their approximate geographic origin. The resulting genetic map forms a triangular structure with a) Finland, b) the Baltic region, Poland and Western Russia, and c) Italy as its vertexes, and with d) Central- and Western Europe in its centre. Inter- and intra- population genetic differences were quantified by the inflation factor lambda (λ) (ranging from 1.00 to 4.21), fixation index (Fst) (ranging from 0.000 to 0.023), and by the number of markers exhibiting significant allele frequency differences in pair-wise population comparisons. The estimated lambda was used to assess the real diminishing impact to association statistics when two distinct populations are merged directly in an analysis. When the PC analysis was confined to the 1,019 Estonian individuals (0.1% of the Estonian population), a fine structure emerged that correlated with the geography of individual counties. With at least two cohorts available from several countries, genetic substructures were investigated in Czech, Finnish, German, Estonian and Italian populations. Together with previously published data, our results allow the creation of a comprehensive European genetic map that will greatly facilitate inter-population genetic studies including genome wide association studies (GWAS).

Mental retardation and autism associated with recurrent 16p11.2 microdeletion: incomplete penetrance and variable expressivity

Since the large implementation of array-based comparative genomic hybridization (array-CGH) in the diagnostic workup of mental retardation (MR), new recurrent copy number variations (CNVs) and novel microdeletion/microduplication syndromes have been described. As more patients are identified carrying microdeletion/microduplication, it has become clear that some genomic disorders have high penetrance but a wide range of phenotypic severity. The recurrent CNVs that are found in multiple unrelated patients are usually associated with a broader range of phenotypes. For instance, the recurrent deletion of the chromosomal region 1q21.1 has been associated with a wide range of phenotypes: from mild to moderate MR, dysmorphic features, microcephaly, cardiac abnormalities and cataract to normal phenotype (Mefford et al. 2008). The same deletions are sometimes transmitted from apparently unaffected parents and are found in 0.02% of controls. Likewise, the most common 16p11.2 microdeletion syndrome has been identified with a similar prevalence (0.3– 0.7%) in large cohorts of patients with intellectual disability or other developmental problems (Bijlsma et al. 2009; Rosenfeld et al. 2010; Shinawi et al. 2010) and in ~0.6% (varying from 0.3% to 1% based on various studies) of all patients with autism spectrum disorder (ASD) (Kumar et al. 2008; Marshall et al. 2008; Weiss et al. 2008). Besides, some individuals carrying the deletion show no obvious developmental or physical abnormalities (Ghebranious et al. 2007; Bijlsma et al. 2009; Shimojima et al. 2009). The 16p11.2 deletion is a recurrent genomic event and a significant risk factor for autism. This genomic disorder also exhibits extensive phenotypic variability and diverse clinical phenotypes. The full extent of phenotypic heterogeneity associated with the 16p11.2 deletion and the factors that modify the clinical phenotypes are currently unknown. Several recent reports suggest a large number of candidate CNVs non-specific to disease involved in the expression of different behaviour phenotypes, including MR, ASD and schizophrenia (SZ) (Guilmatre et al. 2009; Shinawi et al. 2010; Balasubramanian et al. 2011). This implies the existence of shared biological pathways between these neurodevelopmental conditions. The dysfunction of specific neuronal networks of each clinical condition most likely depends on additional genetics, epigenetics and environmental factors which remain to be characterised. Here, we present the clinical and molecular data of two unrelated patients with overlapping 16p11.2 deletions and discuss the function of the genes in this region and the effects of their haploinsufficiency on the clinical features described in the patients. Ž. Ciuladaitė (*) : J. Kasnauskienė : L. Cimbalistienė : E. Preiksaitienė :V. Kucinskas Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Santariskių st. 2, 08661 Vilnius, Lithuania e-mail: zivile.ciuladaite@mf.vu.lt

Familial Distal Monosomy 5p15.3-pter With Trisomy 12q24.2-qter Resulting in Neurodevelopmental Delay and Dysmorphic Features

Developmental delay and brain anomalies leading to significant morbidity and mortality are frequently caused by chromosomal rearrangements. We report on a familial unbalanced translocation resulting in distal monosomy 5p15.3-pter with trisomy 12q24.2-qter in 2 half siblings with cerebral dysgenesis, severe intellectual disability, dysmorphic features, progressive weakness, and atrophy of muscles.

Molecular Karyotyping and Genetic Etiology of Intellectual Disability: Case Reports

Molekulinis kariotipavimas, tai sparciai besivystantis didelės skiriamosios gebos molekulinės citogenetikos metodas, kuris priartina klinikine citogenetiką prie molekulinės diagnostikos ir padeda suprasti žmogaus genomo sudėtingumą, keicia pacientų rutininio istyrimo schemas, plinta ne tik genetikos, bet ir kitose medicinos mokslo ir diagnostikos srityse. Sis naujas diagnostikos metodas sėkmingai pritaikytas nustatant genetines protinio atsilikimo priežastis. Diagnostinis molekulinio kariotipavimo nasumas neaiskios kilmės intelektinės negalios atveju yra daugiau nei 15%, priklausomai nuo mikrolusto skiriamosios gebos bei intelektinės negalios sunkumo. Straipsnyje aprasoma keletas klinikinių atvejų, iliustruojancių molekulinio kariotipavimo naudą - žinomų mikrodelecinių/ mikroduplikacinių sindromų ankstyvą diagnostiką, žinomų genetinių sindromų naujų kritinių genetinių sricių identifikavimą (patogeniskumo mechanizmų papildymą), genų kandidatų, kurių raiskos pokyciai gali būti kritiniai intelektinės negalios etiopatogenezėje, atradimą bei sudėtingų slaptų chromosomos struktūros pokycių identifikavimą. doi:10.5200/sm-hs.2012.010

Establishing the Genetic Diagnosis in Patients with Intellectual Disability: a Case Report of Phelan-Mcdermid Syndrome

In two thirds of patients the cause of intellectual disability is genetical. Introduction of new molecular cytogenetic methods into the diagnostics of intellectual disability demonstrated that the main cause of unknown etiology intellectual disability is chromosomal abnormalities. Array-Comparative Genomic Hybridization reveals submicroscopic aberrations in more than 15% of patients with intellectual disability with normal results from prior conventional cytogenetic testing and number of intellectual disability cases considered as idiopatic forms are now classified as syndromic conditions with clinical recognizable phenotypes. In this article we present the clinical case of Phelan-McDermid syndrome and it‘s early diagnostics by array comparative genome hybridization technique. We discuss the importance of knowing the genetic diagnosis to patient‘s management, treatment and reproductive counselling of the family and prenatal diagnosis. Article in Lithuanian doi:10.5200/sm-hs.2012.011

Predicting a clinical/biochemical phenotype for PKU/MHP patients with PAH gene mutations

Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). In this study, a total of 218 independent PAH chromosomes (109 unrelated patients with PKU residing in Lithuania) were investigated. All 13 exons of the PAH gene of all PKU probands were scanned for DNA alterations by denaturing gradient gel electrophoresis (DGGE). In the cases of a specific DGGE pattern recognized, mutations were identified by direct fluorescent automated sequencing or by restriction enzyme digestion analysis of relevant exons. Twenty-five different PAH gene mutations were identified in Lithuania. We estimated a connection between individual PAH locus mutations and biochemical and metabolic phenotypes in patients in whom the mutant allele acts on its own, i.e., in functionally hemizygous patients and using the assigned value (AV) method to determine the severity of both common and rare mutant alleles, as well as to check a model to predict the combined phenotypic effect of two mutant PAH alleles.