Eglė Preikšaitienė

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

Inflammatory myopathy in a patient with Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is an inflammatory disorder belonging to the recently characterized group of type I interferonopathies. The most consistently affected tissues in AGS are the central nervous system and skin, but various organ systems and tissues have been reported to be affected, pointing to the systemic nature of the disease. Here we describe a patient with AGS due to a homozygous p.Arg114His mutation in the TREX1 gene. The histologically proven inflammatory myopathy in our patient expands the range of clinical features of AGS. Histological signs of muscle biopsies in the proband, and in two other AGS patients described earlier, are similar to those seen in various autoimmune myositises and could be ascribed to inapproapriate IFN I activation. In view of signs of possible mitochondrial damage in AGS, we propose that mitochondrial DNA could be a trigger of autoimmune responses in AGS.

A de novo Pericentric Inversion in Chromosome 4 Associated with Disruption of PITX2 and a Microdeletion in 4p15.2 in a Patient with Axenfeld-Rieger Syndrome and Developmental Delay

Axenfeld-Rieger syndrome (ARS) is a clinically and genetically heterogeneous group of autosomal dominantly inherited malformations that predominantly affect the eye but are also associated with craniofacial dysmorphism and dental abnormalities. A broad spectrum of genetic alterations involving PITX2 and FOXC1 lead to ARS. We report on a 4-year-old girl with clinical features of ARS and developmental delay due to a de novo apparently balanced pericentric inversion in chromosome 4. This report emphasizes that complementary investigations are necessary to precisely characterize chromosomal rearrangements. Elucidation of the exact genetic cause of ARS is important for comprehensive genetic counseling of the family members and for better patient management.

Genomic control process: development and evolution

The Human Genome Project, completed in April 2003, has given the ability to understand the blueprint for building a person. The completed human DNA sequence revealed detailed information about the structure, organisation, and function of the complete set of human genes. Although it is considered the basic set of inheritable instructions for the development of a human being, the DNA sequence does not directly predict the process of development. Instead, genomic control of development is encoded in a complex programme that is distributed in many parts of the genome and referred to in Genomic Control Process as the regulatory genome, which is one of the central themes of this book (Genomic Control Process: Development And Evolution, edited by Isabelle S Peter and Eric H Davidson). The authors provide a conceptual framework that makes the principles by which the genomic control system operates the developmental and evolutionary process accessible. The book is an excellent source of information on the many aspects of the genomic control system, which includes its hierarchy, its logic processing functions, and its structural organisation in the form of gene regulatory networks. The book is organised into seven chapters and begins with the molecular biology of the sequencedependent regulation of gene expression in animal development. The main focus of subsequent chapters is gene regulatory networks: the system of regulatory genes and their encoded interactions that determine the genetic functions to be expressed in time and space. Important topics that are highlighted in the various chapters reveal the genomic strategies for embryonic development, genomic control processes in adult body part formation, and genomic strategies for terminal cell fate specification. Using many diverse examples, the authors illustrate the means by which the transcriptional regulatory system is deployed in the pre-gastrula development of bilateria, explain the genomically encoded mechanisms underlying the formation of body parts, and further explore the differentiation of cell types as the final readout of the preceding spatial specification processes in the development of the body plan. Stating that the structural and functional properties of gene regulatory networks can be accessed mainly by use of models, the authors also consider diverse forms of developmental gene regulatory network models, including topological network models, ODE models of circuit dynamics, and Boolean models of network logic. A special chapter is dedicated to the evolution of bilateria: processes of change and stasis in hierarchical developmental gene regulatory networks. Undeniably, the evolutionary change in body plans must have been caused by evolutionary change in developmental gene regulatory networks. According to the authors, we can understand the process of the development of the body plan of bilateria, or the process of evolution of the body plan of bilateria, only in light of the properties of the encoded developmental gene regulatory networks. The book is reader-friendly, with good headings and brief introductory paragraphs providing the overview to the chapter. Abundant illustrations are detailed, but easy to read and convey essential facts, effectively complementing the text. The discussion is maintained on two different levels, making the book a perfect educational textbook and at the same time providing valuable in-depth information for experts in the field. Each chapter concludes with an extensive list of references to peer-reviewed literature to support further reading. This more-than-400-page book can be highly recommended to a wide range of readers interested in genomics and genomic control mechanisms. The authors Isabelle S Peter and Eric H Davidson should be congratulated on a very valuable work. This excellent book will be a leading reference for the genomic control process for years to come.

Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies

Background. Intellectual disability affects about 1–2% of the general population worldwide, and this is the leading socio-economic problem of health care. The evaluation of the genetic causes of intellectual disability is challenging because these conditions are genetically heterogeneous with many different genetic alterations resulting in clinically indistinguishable phenotypes. Genome wide molecular technologies are effective in a research setting for establishing the new genetic basis of a disease. We describe the first Lithuanian experience in genome-wide CNV detection and whole exome sequencing, presenting the results obtained in the research project UNIGENE. Materials and methods. The patients with developmental delay/intellectual disability have been investigated (n = 66). Diagnostic screening was performed using array-CGH technology. FISH and real time-PCR were used for the confirmation of gene-dose imbalances and investigation of parental samples. Whole exome sequencing using the next generation high throughput NGS technique was used to sequence the samples of 12 selected families. Results. 14 out of 66 patients had pathogenic copy number variants, and one patient had novel likely pathogenic aberration (microdeletion at 4p15.2). Twelve families have been processed for whole exome sequencing. Two identified sequence variants could be classified as pathogenic (in MECP2, CREBBP genes). The other families had several candidate intellectual disability gene variants that are of unclear clinical significance and must be further investigated for possible effect on the molecular pathways of intellectual disability. Conclusions. The genetic heterogeneity of intellectual disability requires genome wide approaches, including detection of chromosomal aberrations by chromosomal microarrays and whole exome sequencing capable of uncovering single gene mutations. This study demonstrates the benefits and challenges that accompany the use of genome wide molecular technologies and provides genotype-phenotype information on 32 patients with chromosomal imbalances and ID candidate sequence variants.

Genotype and phenotype data analysis and visualization

In this paper, we present a comparative analysis of hierarchical clustering and multidimensional scaling methods for genotype and phenotype data analysis. Fishers exact test was applied to determinate dependencies between congenital anomalies. In order to determine the relationship between the dependences of congenital anomalies, deformations, these systems’ micro anomalies and congenital anomalies associated with orofacial clefs, the Spearman and Kendall correlation coefficients were applied. It has been detected which methods are better for genetic data visualization.

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