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Papers by Stylianos Antonarakis

European Heart Journal, Aug 1, 2017

Human Genomics, Jun 28, 2016

The New England journal of medicine, Jan 3, 2018

Background Sporadic arteriovenous malformations of the brain, which are morphologically abnormal ... more Background Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. Methods We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating K...

European Cells and Materials, 2011

Down syndrome is characterized on one hand by extensive phenotypic variability, and on the other ... more Down syndrome is characterized on one hand by extensive phenotypic variability, and on the other by a recognizable dysmorphic syndrome. Here we compare whole transcriptomes by RNA-Seq of primary fibroblasts from 8 Down Syndrome (DS) and 8 Normal (N) unrelated individuals age and sex matched in order to study variation in gene expression. Gene by gene comparison of the whole transcriptomes revealed a remarkable decreased variance in gene expression level in DS versus N (median of the distribution of ratios of variances in DS to N is 0.64, which is less than the expected 1; P value < 1*10-16, Wilcoxon signed-rank test). The decreased variance in DS could not be explained by differences in mean expression levels between DS and N. This effect is present for genes on each individual chromosome (except chromosome 21) and for different sets of genes studied. The effect is also robust to the number of passages of fibroblasts. The effect is stronger in young (<2 years) versus old (>...

Archives of Disease in Childhood, 2012

Molecular Biology and Evolution, 2012

Nature genetics, Jan 7, 2016

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is pr... more Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BC...

American journal of human genetics, Jan 24, 2016

Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. I... more Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analyzed acr...

European Journal of Human Genetics Ejhg, Apr 11, 2012

Molecular Biology Medicine, 1990

We have used molecular and cytogenetic methods to study the derivation of a ring chromosome 13 in... more We have used molecular and cytogenetic methods to study the derivation of a ring chromosome 13 in the fetus of a woman mosaic for a translocation chromosome 13. DNA analysis showed that the translocation chromosome was a Robertsonian translocation, not an isochromosome. We suggest that the ring is derived from the translocation chromosome by breaks in both long arms and subsequent reunion, r(13) (q12q14).

$Research paper thumbnail of The restructuring and future of {open_quotes}Mendelian Inheritance in Man{close_quotes} (MIM)$

Amer J Hum Genet, 1994

ABSTRACT

Medicine, Mar 1, 1986

Abnormalities in the parathyroid hormone (PTH) gene as a cause of hypoparathyroidism were evaluat... more Abnormalities in the parathyroid hormone (PTH) gene as a cause of hypoparathyroidism were evaluated by linkage analysis with DNA polymorphisms adjacent to the PTH gene in 8 families in which members were affected with familial isolated hypoparathyroidism (FIH). We found that in none of the 23 affected individuals was there absence of the parathyroid hormone gene or abnormal restriction patterns to suggest recognizable deletions, insertions, or rearrangements. To determine if subtle mutations within the PTH gene were associated with hypoparathyroidism in these families, we used the Pst I and Taq I restriction-site polymorphisms in linkage analysis as markers to differentiate between PTH alleles. In 4 families, affected sibs inherited different PTH gene alleles, implying that hypoparathyroidism was not due to an abnormality in the PTH gene. In 2 other families, linkage analysis was uninformative because of inability to differentiate between PTH alleles. In 2 families, concordance was found between the inheritance of hypoparathyroidism and specific PTH alleles in affected members, suggesting that in these families, hypoparathyroidism may be due to an alteration in or near the PTH structural gene. We conclude that FIH is a diverse group of disorders and is characterized by genetic and molecular heterogeneity. In some forms of FIH the mutation that leads to PTH deficiency does not lie within the region of the structural gene for PTH. Linkage analysis using DNA polymorphisms within the PTH gene is of benefit in identifying individuals with disorders of PTH secretion or synthesis in whom DNA sequencing and expression studies of the PTH gene might succeed in establishing the molecular basis of the disease.

The Quarterly Review of Biology, Dec 1, 1975

The American Journal of Human Genetics, Mar 1, 1992

The International Journal of Developmental Biology, 2002

In the year 2000 we celebrated the sequencing of the entire long arm of human chromosome 21. This... more In the year 2000 we celebrated the sequencing of the entire long arm of human chromosome 21. This achievement now provides unprecedented opportunities to understand the molecular pathophysiology of trisomy 21, elucidate the mechanisms of all monogenic disorders of chromosome 21, and discover genes and functional sequence variations that predispose to common complex disorders. All of that requires the functional analysis of gene products in model organisms, and the determination of the sequence variation of this chromosome.