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).

The use of high-resolution microarray technology for investigation of patients with intellectual disability and/or congenital anomalies provided the unique possibility to identify new microdeletion/microduplication syndromes and discover the dosage sensitive genes, which are implicated in the manifestation of various genetic conditions. Microduplication of the 7p22.1 region, 1.7 Mb in size, has very recently been reported, representing the smallest interstitional 7p duplication, associated with specific facial features and speech delay. We report on a patient with an even smaller 7p22.1 de novo microduplication, 1 Mb in size, detected in a 14.5-year-old patient with mild intellectual disability and similar facial dysmorphism, including macrocephaly, ocular hypertelorism, low-set ears, and other features. There are 15 RefSeq genes included in this duplication. ACTB gene is a strong candidate gene for the alteration of craniofacial development. Further cases with similar duplications will contribute to the delineation of a potential new microduplication syndrome of 7p22.1.

We report on a 15-year-old patient with hyperactivity, intellectual disability and severe speech developmental delay. An array CGH analysis revealed de novo 2q34 deletion, 958 kb in size, involving a single protein coding gene ERBB4 (position 212,505,294-213,463,152; NCBI build 36). The ERBB4 gene is important in numerous neurobiological processes in both the developing and the adult brain. The NRG1-ERBB4 signaling pathway has been recently implicated in the pathophysiology of schizophrenia and epilepsy. Many risk haplotypes were identified in several studies across different populations. The severe clinical consequences in our patient demonstrate that the haploinsufficiency of ERBB4 is crucial for intellectual and cognitive function. These observations are compatible with previously reported results.

We report the spectrum of phenylalanine hydroxylase (PAH) gene mutations in patients with phenylketonuria (PKU) residing in Lithuania. A total of 184 independent chromosomes was investigated. R408W mutation was first analysed through restriction enzyme digestion of exon 12. The remaining uncharacterised PKU chromosomes were analysed by scanning the whole coding sequence of PAH gene by multiplex 'broad range' denaturing gradient gel electrophoresis. Mutations were identified by fluorescent automated sequencing or by restriction enzyme digestion analysis if an abnormal DGGE pattern was recognised. 21 different mutations were identified for 175 PKU chromosomes, with a mutation detection rate of 95%. The most common ones were R408W (73.5% chromosomes) and R158Q (7.0% chromosomes) whereas the remaining mutations appeared to be rare (relative frequencies 0.5%-2%). The high mutation detection rate obtained is an evidence of the efficiency of PAH genetic testing achieved in Lithuania. Moreover, the definition of the PKU mutation profile in the Lithuanian population will allow to perform a genotype-phenotype correlation study thus making feasible genotyped-based prediction of the biochemical phenotype in newborns with hyperphenylalaninemia. This may be useful for refining diagnosis and anticipating dietary requirements.

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