Nouvelles données en génétique chromosomique

Les méthodes modernes d’analyse du génome ont permis d’aborder des questions posées de longue date telles que les bases moléculaires des anomalies chromosomiques de structure ou la diathèse (prédisposition) aux aneuploïdies. L’architecture du génome révélée par le séquençage permet d’expliquer la récurrence de microremaniements par échange homologue non-allélique entre des répétitions segmentaires formées au cours de l’évolution des primates. Cette particularité structurale du génome a conduit à l’individualisation d’une nouvelle classe de maladies génétiques appelées désordres génomiques par opposition aux maladies géniques dues à des mutations intragéniques. L’étude de l’origine parentale et cellulaire des aneuploïdies éclaire d’un jour nouveau les mécanismes de contrôle de la méiose différents chez l’homme et chez la femme, ainsi que le rôle majeur de l’âge maternel et de la recombinaison pour la répartition méiotique correcte des chromosomes. Ces nouvelles données apportent des clés essentielles pour la compréhension des pathologies chromosomiques chez l’homme.Novel methods allowing to analyze the human genome make it possible to assess old questions such as the molecular basis of structural chromosome anomalies and the diathesis to aneuploidy. The architecture of the human genome as unravelled by the human genome sequencing project allows to explain the recurrence of microdeletions and microduplications caused by a non allelic homologous recombination involving segmental duplications created during the evolution of primates. This structural feature of the human genome is associated with a novel class of genetic diseases called genomic disorders as opposed to genetic diseases due to gene mutations. The study of the parental and cellular origin of aneuploidy shed new light on the different mechanisms controlling meiosis in man and woman. In addition it contributes to define the role of maternal age and genetic recombination on the behavior of chromosomes during meiosis. These new data greatly contribute to our understanding of human chromosomal diseases

A child with multiple congenital anomalies and karyotype 46,XY,del(14)(q31q32.3): Further delineation of chromosome 14 interstitial deletion syndrome

We report on an infant with a multiple congenital anomaly syndrome and severe developmental delay in association with a previously undescribed de novo interstitial deletion of chromosome 14 [karyotype: 46,XY,del(14) (q31q32.3)]. Comparison of the presented patient with previously reported cases of interstitial and terminal chromosome 14q deletions provides a group of patients monosomic for various overlapping portions of the distal half of chromosome 14q and suggests a limited similarity in phenotype among patients with common deleted 14q segments. All patients with distal 14q deletions were developmentally delayed, most were microcephalic and failed to thrive. Most of the patient's anomalies were limited to the face and head. Few major internal congenital anomalies were observed. These comparisons serve to further clarify possible associations of subchromosomal aberrations with specific phenotypes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38252/1/1320370409_ftp.pd

Whole gene deletion of EBF3 supporting haploinsufficiency of this gene as a mechanism of neurodevelopmental disease

Mutations in early B cell factor 3 (EBF3) were recently described in patients with a neurodevelopmental disorder (NDD) that includes developmental delay/intellectual disability, ataxia, hypotonia, speech impairment, strabismus, genitourinary abnormalities, and mild facial dysmorphisms. Several large 10q terminal and interstitial deletions affecting many genes and including EBF3 have been described in the literature. However, small deletions (<1 MB) affecting almost exclusively EBF3 are not commonlyreported. We performed array comparative genomic hybridization (aCGH) (Agilent 180K) and quantitative PCR analysis in a female patient with intellectual disability. A clinical comparison between our patient and overlapping cases reported in the literature was also made. The patient carries a de novo 600 Kb deletion at 10q26.3 affecting the MGMT, EBF3, and GLRX genes. The patient has severe intellectual disability, language impairment, conductive hearing loss, hypotonia, vision alterations, triangular face, short stature, and behavior problems. This presentation overlaps that reported for patients carrying EBF3 heterozygous point mutations, as well as literature reports of patients carrying large 10qter deletions. Our results and the literature review suggest that EBF3 haploinsufficiency is a key contributor to the common aspects of the phenotype presented by patients bearing point mutations and indels in this gene, given that deletions affecting the entire gene (alone or in addition to other genes) are causative of a similar syndrome, including intellectual disability (ID) with associated neurological symptoms and particular facial dysmorphisms.FCT—Fundação para a Ciência e a Tecnologia within the projects and scholarships (PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012). This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnershi p Agreement, through the European Regional Development Fund (FEDER).info:eu-repo/semantics/publishedVersio

A 6q14.1-q15 microdeletion in a male patient with severe autistic disorder, lack of oral language, and dysmorphic features with concomitant presence of a maternally inherited Xp22.31 copy number gain

We report on a male patient with severe autistic disorder, lack of oral language, and dysmorphic features who carries a rare interstitial microdeletion of 4.96 Mb at chromosome 6q14.1‐q15. The patient also harbors a maternally inherited copy number gain of 1.69 Mb at chromosome Xp22.31, whose pathogenicity is under debateS

The phenotypic and cytogenetic spectrum of partial trisomy 9

A new patient with trisomy for the chromosome segment 9pter→q22 is compared to 19 previously reported cases of partial trisomy 9. Manifestations such as microcephaly, prominent nasal root, bulbous nose, and down-turned corners of the mouth are common to patients with trisomic segments extending from 9p21 to 9q13, while intra-uterine growth retardation, cleft lip/palate, skeletal anomalies, and heart defects are more common with trisomic segments extending through 9q22-9q32. A graphic method illustrates this progression in the partial trisomy 9 malformation spectrum as the triplicated chromosome region extends from bands 9q21 to 9q32. More severe and random defects are observed with complete trisomy 9 or tetrasomy 9p, suggesting an extreme excess of material greatly increases developmental variability.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38237/1/1320200211_ftp.pd

Evaluation of A2BP1 as an Obesity Gene

OBJECTIVE-A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity. RESEARCH DESIGN AND METHODS-Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication. Published GWAS data across A2BP1 were additionally analyzed in French adult (n = 1,426) and children case/control subjects (n = 1,392) (Meyre et al. Nat Genet 2009;41:157-159). Selected variants were genotyped in two additional samples of Caucasians (Amish, n = 1,149, and German children case/control subjects, n = 998) and one additional Native American (n = 2,531) sample. Small interfering RNA was used to knockdown A2bp1 message levels in mouse embryonic hypothalamus cells. RESULTS-No single variant in A2BP1 was reproducibly associated with obesity across the different populations. However, different variants within intron 1 of A2BP1 were associated with BMI in full-heritage Pima Indians (rs10500331, P = 1.9 x 10(-7)) and obesity in French Caucasian adult (rs4786847, P = 1.9 x 10(-10)) and children (rs8054147, P = 9.2 x 10(-6)) case/control subjects. Reduction of A2bp1 in mouse embryonic hypothalamus cells decreased expression of Atxn2, Insr, and Mc4r. CONCLUSIONS-Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway. Diabetes 59:2837-2845, 201

Distal Xq duplication and functional Xq disomy

Distal Xq duplications refer to chromosomal disorders resulting from involvement of the long arm of the X chromosome (Xq). Clinical manifestations widely vary depending on the gender of the patient and on the gene content of the duplicated segment. Prevalence of Xq duplications remains unknown. About 40 cases of Xq28 functional disomy due to cytogenetically visible rearrangements, and about 50 cases of cryptic duplications encompassing the MECP2 gene have been reported. The most frequently reported distal duplications involve the Xq28 segment and yield a recognisable phenotype including distinctive facial features (premature closure of the fontanels or ridged metopic suture, broad face with full cheeks, epicanthal folds, large ears, small and open mouth, ear anomalies, pointed nose, abnormal palate and facial hypotonia), major axial hypotonia, severe developmental delay, severe feeding difficulties, abnormal genitalia and proneness to infections. Xq duplications may be caused either by an intrachromosomal duplication or an unbalanced X/Y or X/autosome translocation. In XY males, structural X disomy always results in functional disomy. In females, failure of X chromosome dosage compensation could result from a variety of mechanisms, including an unfavourable pattern of inactivation, a breakpoint separating an X segment from the X-inactivation centre in cis, or a small ring chromosome. The MECP2 gene in Xq28 is the most important dosage-sensitive gene responsible for the abnormal phenotype in duplications of distal Xq. Diagnosis is based on clinical features and is confirmed by CGH array techniques. Differential diagnoses include Prader-Willi syndrome and Alpha thalassaemia-mental retardation, X linked (ATR-X). The recurrence risk is significant if a structural rearrangement is present in one of the parent, the most frequent situation being that of an intrachromosomal duplication inherited from the mother. Prenatal diagnosis is performed by cytogenetic testing including FISH and/or DNA quantification methods. Management is multi-specialist and only symptomatic, with special attention to prevention of malnutrition and recurrent infections. Educational and rehabilitation support should be offered to all patients