¿Qué puede esconder el retraso global del desarrollo? A propósito de un caso de causa genética / What can Global Developmental Delay Conceal? Apropos of a Case with a Genetic Cause

Se presenta un niño de 6 años con antecedente de retraso del lenguaje que llevó a sus padres a realizar múltiples consultas. En un primer momento, su cuadro fue interpretado como parte de un retraso global del desarrollo. Posteriormente, el paciente presentó convulsiones y episodios de descompensación metabólica, comenzando desde entonces su seguimiento por los Servicios de neurología, genética y metabolismo. Finalmente, tras varios estudios complementarios, por medio de un exoma trío se arribó al diagnóstico de síndrome de microduplicación del cromosoma 7q11.23, lo que justifica tanto el retraso global de desarrollo del paciente como su clínica neurológica. (AU)

A six-year-old boy presents with a history of language delay that led his parents to make multiple consultations. At first, we interpreted his condition as part of a global developmental delay. Subsequently, the patient presented seizures and episodes of metabolic decompensation, and since then, he had to be followed up by neurology, genetics, and metabolism services. Finally, after several complementary studies, following a trio exome analysis, we diagnosed chromosome 7q11.23 microduplication syndrome, which explains his global developmental delay and neurological symptoms. (AU)

Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families.

Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

Growth assessment in children with Williams-Beuren syndrome: a systematic review.

Williams-Beuren syndrome (WBS) is a rare genetic disease caused by a sporadic heterozygous microdeletion in 7q11.23. It is characterized by distinctive facial appearance, cardiopathy, short stature, intellectual disability, and endocrine abnormalities. To evaluate the growth pattern of patients with WBS and to identify the prevalence of malnutrition, overweight, and obesity in this population, a systematic review of studies published in English, between 1987 and 2018, was performed following the PRISMA protocol using the PubMed, Cochrane, and BIREME databases. Original articles and articles that evaluated growth status using weight, or height, or head circumference (HC), or body mass index (BMI) of individuals with WBS were included. Case reports, articles with data from other syndromes, and articles that did not present as a central theme the evaluation of growth were not included. WBS presented specific growth pattern, characterized by intrauterine growth restriction, low weight, length, and HC at birth. This global growth delay persisted during childhood and adolescence. BMI was not different to the reference population, and obesity was not observed in childhood. The mechanisms that determine this typical growth pattern are not totally clear; however, the typical pubertal development of these patients and the intrinsic and secondary lesions caused by microdeletion at 7q11.23 seem to be the major factors involved. Conclusion: Patients with WBS have a growth pattern different from the general reference population. The reference charts for normal population should not be used for WBS patients because it often underestimate their growth. Specific growth charts for WBS patients are necessary.

Williams-Beuren syndrome in Mexican patients confirmed by FISH and assessed by aCGH.

Williams-Beuren syndrome (WBS) has a prevalence of 1/7500-20000 live births and results principally from a de novo deletion in 7q11.23 with a length of 1.5 Mb or 1.8 Mb. This study aimed to determine the frequency of 7q11.23 deletion, size of the segment lost, and involved genes in 47 patients with a clinical diagnosis of WBS and analysed by fluorescence in situ hybridization (FISH); among them, 31 had the expected deletion. Micro-array comparative genomic hybridization (aCGH) confirmed the loss in all 18 positive-patients tested: 14 patients had a 1.5 Mb deletion with the same breakpoints at 7q11.23 (hg19: 72726578-74139390) and comprising 24 coding genes from TRIM50 to GTF2I. Four patients showed an atypical deletion: two had a 1.6 Mb loss encompassing 27 coding genes, from NSUN5 to GTF2IRD2; another had a 1.7 Mb deletion involving 27 coding genes, from POM121 to GTF2I; the remaining patient presented a deletion of 1.2 Mb that included 21 coding genes from POM121 to LIMK1. aCGH confirmed the lack of deletion in 5/16 negative-patients by FISH. All 47 patients had the characteristic facial phenotype of WBS and 45 of 47 had the typical behavioural and developmental abnormalities. Our observations further confirm that patients with a classical deletion present a typical WBS phenotype, whereas those with a high (criteria of the American Association of Pediatrics, APP) clinical score but lacking the expected deletion may harbour an ELN point mutation. Overall, the concomitant CNVs appeared to be incidental findings.

Características otorrinolaringológicas en niños con trisomía 21: un estudio de 171 pacientes en el Hospital Infantil de México Federico Gómez / Otolaryngological features in children with trisomy 21: a study of 171 patients at the Hospital Infantil de México Federico Gómez

Resumen Introducción: Los niños con trisomía 21 enfrentan una amplia gama de problemas en la región de la cabeza y el cuello, por lo cual es importante reconocer las manifestaciones otorrinolaringológicas que presentan, así como su apropiado manejo. Métodos: Estudio de serie de casos retrospectivo de pacientes pediátricos con trisomía 21. De cada caso se analizó el espectro de manifestaciones otorrinolaringológicas, el manejo establecido y los resultados. Resultados: Se incluyeron 171 niños. La edad media de la primera valoración por otorrinolaringología en la institución fue de 7.2 ± 4.2 años. Las manifestaciones otológicas más frecuentes fueron la estenosis del conducto auditivo externo y la disfunción de la trompa de Eustaquio. Más de la mitad de los pacientes (63 %) presentaron hipoacusia, principalmente de tipo conductivo bilateral, y hasta el 75 % de los pacientes con afectación otológica requirieron algún procedimiento quirúrgico. Las manifestaciones rinológicas más comunes fueron la rinosinusitis crónica y la rinitis alérgica. La apnea obstructiva del sueño estuvo presente en el 30% de los pacientes. El tratamiento principal fue la amigdalectomía, seguida del tratamiento con dispositivos de presión positiva de la vía aérea. Menos del 5 % de los pacientes presentaron un compromiso laríngeo. Conclusiones: Los pacientes pediátricos con trisomía 21 deben ser remitidos sistemáticamente a una evaluación otorrinolaringológica periódica, debido a la alta incidencia de manifestaciones en esta región. Se deben ofrecer tratamientos oportunos para mejorar su salud y calidad de vida.

Abstract Introduction: Children with trisomy 21 face a wide range of conditions in the head and neck region, for which it is important that physicians are aware and have a strong understanding of the ear, nose, and throat (ENT) disorders, and their management as well. Methods: Retrospective case series of pediatric patients with trisomy 21. The spectrum of otolaryngological manifestations, their management, and outcomes of each case were analysed. Results: One hundred and seventeen pediatric patients were included. The mean age was 7.2 ± 4.2 years. More than half of the patients (63 %) had hearing loss (HL). The most frequent presentation was conductive HL, predominating the mild and bilateral type. The most common otological manifestations found were external ear canal stenosis and Eustachian tube dysfunction. Up to 75 % of the patients with otologic involvement required some surgical procedure. The most common rhinological manifestations were chronic rhinosinusitis and allergic rhinitis. Obstructive sleep apnea (OSA) was present in 30% of all patients, which main treatment was tonsillectomy, followed by continuous positive and biphasic positive airway pressure treatments. Less than 5 % of the patients presented a laryngeal compromise. Conclusions: Pediatric patients with trisomy 21 systematically should be referred to periodic ENT assessment due to the high incidence of manifestations in this region. Timely treatments should be offered in order to improve the health and the quality of life of the patient.

[Atypical deletions in Williams-Beuren syndrome]. / Deleciones atípicas en el síndrome Williams-Beuren.

The Williams-Beuren (SWB; OMIM 194050) syndrome is an autosomal dominant multisystem disorder that occurs in ~ 1 in 20,000 live births and results from a 7q11.23 deletion spanning ~ 28 genes. This deletion is caused by a nonallelic homologous recombination (NAHR) between low copy repeats present therein. The SWB phenotype is characterized by neonatal hypercalcemia, mental disability, distinctive personality and cognitive profile, short stature, dysmorphic facies, connective tissue disorders and supravalvular aortic stenosis. Ninety percent of the deletions are of 1.5 Mb, 8% of 1.84Mb, and only 2% are atypical. Although only ~ 40 atypical deletions have been described, they have contributed to clarify the genotype-phenotype correlation and allowed for a more integrative management. In this review we highlight the importance of detecting atypical deletions in patients with SWB.

El síndrome Williams-Beuren (SWB; OMIM 194050) es un trastorno multisistémico autosómico dominante que ocurre en ~ 1 de cada 20 000 nacidos vivos, y se debe a una deleción en 7q11.23 de ~ 28 genes. Esta deleción resulta de una recombinación homóloga no alélica entre repeticiones de bajo número de copias presentes en dicha región. El fenotipo SWB se caracteriza por hipercalcemia neonatal, discapacidad mental, personalidad y perfil cognitivo distintivos, baja estatura, facies dismórficas, trastornos del tejido conectivo y estenosis aórtica supravalvular. El 90% de las deleciones son de 1.5 Mb, 8% de 1.84 Mb, y solo el 2% son atípicas. Aunque solo se han descrito ~ 40 deleciones atípicas, estas han contribuido a esclarecer la correlación genotipo-fenotipo y permitido un manejo integral. En esta revisión se destaca la importancia de la detección de deleciones atípicas en pacientes con SWB.

Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families.

Cardiovascular disorders including ischemic stroke (IS) and myocardial infarction (MI) are heritable; however, few replicated loci have been identified. One strategy to identify loci influencing these complex disorders is to study subclinical phenotypes, such as carotid bifurcation intima-media thickness (bIMT). We have previously shown bIMT to be heritable and found evidence for linkage and association with common variants on chromosome 7p for bIMT. In this study, we aimed to characterize contributions of rare variants (RVs) in 7p to bIMT. To achieve this aim, we sequenced the 1 LOD unit down region on 7p in nine extended families from the Dominican Republic (DR) with strong evidence for linkage to bIMT. We then performed the family-based sequence kernel association test (famSKAT) on genes within the 7p region. Analyses were restricted to single nucleotide variants (SNVs) with population based minor allele frequency (MAF) <5%. We first analyzed all exonic RVs and then the subset of only non-synonymous RVs. There were 68 genes in our analyses. Nucleotide-binding oligomerization domain (NOD1) was the most significantly associated gene when analyzing exonic RVs (famSKAT p = 9.2x10-4; number of SNVs = 14). We achieved suggestive replication of NOD1 in an independent sample of twelve extended families from the DR (p = 0.055). Our study provides suggestive statistical evidence for a role of rare variants in NOD1 in bIMT. Studies in mice have shown Nod1 to play a role in heart function and atherosclerosis, providing biologic plausibility for a role in bIMT thus making NOD1 an excellent bIMT candidate.

Chromosome 7 translocation breakpoints in male carriers: clinical features and implications for genetic counseling.

Balanced reciprocal translocations are associated with reproductive failure. Some reciprocal translocation carriers exhibit azoospermia or oligozoospermia, and an association exists between these chromosomal abnormalities and recurrent abortion. Previous reports have indicated the involvement of chromosome 7 translocations in male infertility and recurrent miscarriage. A translocation breakpoint can occur within an important gene, interrupting its structure and leading to male infertility. However, clinical characteristics resulting from chromosome 7 translocation breakpoints have not been studied. Here, we report such breakpoints and their associated clinical features, to enable informed genetic counseling of carriers. Balanced reciprocal translocations were found in 1.57% of the tested patients. Among these 82 individuals, 14 (17.07%) carried a chromosome 7 translocation, of which, five presented with pregestational infertility and clinical manifestations of oligozoospermia or necrospermia, while nine presented with gestational infertility (i.e., were able to conceive, but often resulting in miscarriage). Breakpoints at 7q31 and 7q36 were associated with pregestational infertility, whereas those at 7p10, 7q21.2, 7q22, and 7q32 were connected to gestational infertility. However, the breakpoint at 7p15 was associated with both. Chromosome 7 translocation carriers with pregestational or gestational infertility should be counseled on chromosomal breakpoints and the various molecular technologies available for assisted reproduction.

COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia.

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 Δ1-8), which account for ~30% of all ΔIKZF1, we aimed at investigating the genomic scenery of IKZF1 Δ1-8. Six samples of cases with IKZF1 Δ1-8 were analyzed by microarray assay, which identified monosomy 7, isochromosome 7q, and large interstitial deletions presenting breakpoints within COBL gene. Then, we established a multiplex ligation-probe amplification (MLPA) assay and screened copy number alterations within chromosome 7 in 43 diagnostic samples with IKZF1 Δ1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 Δ1-8. Detailed analysis using long distance inverse PCR showed that six patients (16%) had large interstitial deletions starting within intronic regions of COBL at diagnosis, which is ~611 Kb downstream of IKZF1, suggesting that COBL is a hotspot for ΔIKZF1. We also investigated a series of 25 intragenic deletions (Δ2-8, Δ3-8 or Δ4-8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ΔIKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 Δ1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ΔIKZF1.

Deletion 21q22.3 and duplication 7q35q36.3 in a Colombian girl: a case report.

BACKGROUND: Genetic disorders are a major cause in the etiology of cases with intellectual disability; however, analysis by a conventional technique such as cytogenetic karyotyping only allows the detection of chromosomal alterations in approximately 9.5 % of cases. The inclusion of new technologies such as high resolution microarray analysis has allowed the study of alterations in chromosomal segments that are less than 5 Mb in length; this has led to an increase in the diagnosis of these patients of up to 25 %. CASE PRESENTATION: We report the first case of an 8-year-old Colombian girl of mixed race ancestry (Mestizo), with clinical features that include: delayed psychomotor and language development, intellectual disability, upward slanting palpebral fissures, divergent strabismus, low-set and rotated ears, tall and broad nasal bridge, flat philtrum, bifid uvula, posterior cleft palate, increased anteroposterior diameter of her chest, congenital heart defect type interventricular communication, scoliosis, and umbilical hernia. Genetic analysis was performed using comparative genomic hybridization array, which evidenced the deletion of a region of approximately 3.608 Mb on chromosome 21q22.3, and a duplication of 12.326 Mb on chromosome 7q35q36.3, these alterations affect approximately 112 and 186 genes, respectively. CONCLUSIONS: To date, this is the first report of an associated terminal deletion of 21q and 7q duplication in a patient with delayed psychomotor development and intellectual disability. We consider that future implementation of exome and RNA sequencing techniques, and analysis of their proteomic expression in a clinical context could lead to better analysis and interpretation of the genotype-phenotype correlation in cases similar to that described.

[Chromosome 7q11.23 duplication syndrome. First reported case in Latin America]. / Síndrome de duplicación 7q11.23. Primer caso descrito en América Latina.

7q11.23 duplication syndrome is a disease caused by duplication of a region of chromosome 7 comprising 26 genes. The first case described in the literature was reported by Somerville et al. in 2005, who described a patient with dolichocephaly, high and narrow forehead, long eyelashes, high and wide nose, short philtrum, high arched palate, dental malocclusion, retrognathia, and severe language delay. We report the case of a Colombian patient with 7q11.23 duplication by comparative genomic hybridization techniques, and classical clinical findings, this being the first reported case in Colombia and Latin America.

El síndrome de duplicación 7q11.23 es una patología causada por la duplicación de una región del cromosoma 7 que comprende 26 genes. El primer caso descrito en la literatura fue reportado por Somerville et al., en el año 2005, quienes describieron un paciente con dolicocefalia, frente alta y estrecha, pestanas largas, nariz alta y ancha, filtrum corto, paladar ojival, maloclusión dental, retrognatia y retardo grave en el lenguaje. Presentamos una paciente colombiana con hallazgo de duplicación 7q11.23 mediante técnicas de hibridación genómica comparativa y hallazgos clínicos clásicos. Este es el primer caso comunicado en Colombia y en América Latina.

Síndrome de duplicación 7q11. 23: Primer caso descrito en América Latina / Chromosome 7q11. 23 duplication syndrome: First reported case in Latin America

El síndrome de duplicación 7q11.23 es una patología causada por la duplicación de una región del cromosoma 7 que comprende 26 genes. El primer caso descrito en la literatura fue reportado por Somerville et al., en el año 2005, quienes describieron un paciente con dolicocefalia, frente alta y estrecha, pestanas largas, nariz alta y ancha, filtrum corto, paladar ojival, maloclusión dental, retrognatia y retardo grave en el lenguaje. Presentamos una paciente colombiana con hallazgo de duplicación 7q11.23 mediante técnicas de hibridación genómica comparativa y hallazgos clínicos clásicos. Este es el primer caso comunicado en Colombia y en América Latina.

7q11.23 duplication syndrome is a disease caused by duplication of a region of chromosome 7 comprising 26 genes. The first case described in the literature was reported by Somerville et al. in 2005, who described a patient with dolichocephaly, high and narrow forehead, long eyelashes, high and wide nose, short philtrum, high arched palate, dental malocclusion, retrognathia, and severe language delay. We report the case of a Colombian patient with 7q11.23 duplication by comparative genomic hybridization techniques, and classical clinical findings, this being the first reported case in Colombia and Latin America.

Rare genomic rearrangement in a boy with Williams-Beuren syndrome associated to XYY syndrome and intriguing behavior.

Williams-Beuren syndrome (WBS) is caused by a hemizygous contiguous gene microdeletion of 1.55-1.84 Mb at 7q11.23 region. Approximately, 28 genes have been shown to contribute to classical phenotype of SWB with presence of dysmorphic facial features, supravalvular aortic stenosis (SVAS), intellectual disability, and overfriendliness. With the use of Microarray-based comparative genomic hybridization and other molecular cytogenetic techniques, is possible define with more accuracy partial or atypical deletion and refine the genotype-phenotype correlation. Here, we report on a rare genomic structural rearrangement in a boy with atypical deletion in 7q11.23 and XYY syndrome with characteristic clinical signs, but not sufficient for the diagnosis of WBS. Cytogenetic analysis of G-banding showed a karyotype 47,XYY. Analysis of DNA with the technique of MLPA (Multiplex Ligation-dependent Probe Amplification) using kits a combination of kits (P064, P036, P070, and P029) identified an atypical deletion on 7q11.23. In addition, high resolution SNP Oligonucleotide Microarray Analysis (SNP-array) confirmed the alterations found by MLPA and revealed others pathogenic CNVs, in the chromosomes 7 and X. The present report demonstrates an association not yet described in literature, between Williams-Beuren syndrome and 47,XYY. The identification of atypical deletion in 7q11.23 concomitant to additional pathogenic CNVs in others genomic regions allows a better comprehension of clinical consequences of atypical genomic rearrangements.

A Novel 23.1 Mb Interstitial Deletion Involving 7q22.3q32.1 in a Girl with Short Stature, Motor Delay, and Craniofacial Dysmorphism.

Interstitial deletions of 7q show a wide phenotypic spectrum that varies with respect to the location and size of the deleted region. They lead to craniofacial dysmorphism with intellectual disability, growth retardation, and various congenital defects. Here, a Mexican girl with microcephaly, facial dysmorphism, short stature, hand anomalies, and intellectual disability was analyzed by CytoScan HD array. Her phenotype was associated with a de novo 7q22.3q32.1 deletion involving 109 loci, 57 of them listed in the OMIM database. This novel deletion increases the knowledge of the variability in the rupture sites of the region and expands the spectrum of molecular and clinical defects of the 7q deletion syndrome.

Chromosome band 7q34 deletions resulting in KIAA1549-BRAF and FAM131B-BRAF fusions in pediatric low-grade Gliomas.

The majority of pediatric low-grade gliomas (LGGs) are characterized by constitutive activation of the mitogen-activated protein kinase (MAPK) pathway through various mechanisms including BRAF mutations, inactivation of NF1, and KIAA1549-BRAF and FAM131B-BRAF fusions. The KIAA1549-BRAF fusion typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. In the present study, single nucleotide polymorphism (SNP)-based array analysis of three LGGs demonstrated deletions in 7q34 that resulted in a BRAF fusion. Case 1 was likely a pilocytic astrocytoma (PA) with three deletions in 7q33q34 and an exon 15-9 KIAA1549-BRAF fusion. SNP array analysis of case 2, a possible dysembryoplastic neuroepithelial tumor (DNT), revealed a 2.6 Mb deletion, which included the 5' end of BRAF and extended to the 3' end of FAM131B. In case 3, deletions involving BRAF and FAM131B were observed in both a primary and a recurrent PA. RNA-based sequence analysis of cases 2 and 3 confirmed a fusion between FAM131B exon 2 and BRAF exon 9. The presence of fusion transcripts in these three LGGs highlights the utility of SNP array analysis to identify deletions that are suggestive of fusion proteins. BRAF fusions can result from multiple non-overlapping deletions, suggesting various complex mechanisms of formation.

Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study.

MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value = 1.7 × 10(-4) ; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value = 5.38 × 10(-3) ; OR = 0.56, 95% CI = 0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value = 5.40 × 10(-3) ; OR = 1.41, 95% CI = 1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.

Cytogenomic and phenotypic analysis in low-level monosomy 7 mosaicism with non-supernumerary ring chromosome 7.

We present the literature review of ring chromosome 7 and clinical, cytogenetic and fine molecular mapping of the first postnatal report of a male child with a non-supernumerary ring chromosome 7, r(7). The patient had dysmorphic features, developmental delay, dermatologic lesions with variable pigmentation, hypogenitalism, lumbar dextroscoliosis, cerebellar and ophthalmological abnormalities, and melanocytic congenital nevi. Cytogenetic analysis of peripheral blood and the nevus sample showed the presence of three different cell lines r(7), monosomy 7, and duplicated r(7) (idic r(7)), while findings on fibroblasts from both light and dark skin showed only mosaicism with r(7) and monosomy 7 cell lines in various proportions. FISH assay of the ring chromosome showed subtelomeric loss in both chromosome arms in all tissues studied. Analysis by genome-wide single-nucleotide polymorphism array showed a 0.8 Mb deletion in 7p22.3 (involving eight genes) and a 7.5 Mb deletion in 7q36 (involving 29 genes including some involved in genital and central nervous system development). The combination of results from our karyotypic and array analyses enabled us to establish an accurate genotype-phenotype relationship.

Mutation analysis of a Chinese pedigree with triphalangeal thumb-polysyndactyly syndrome.

Triphalangeal thumb-polysyndactyly syndrome (TPTPS) is an autosomal dominant limb disorder with triphalangeal thumbs, polysyndactyly, and syndactyly. In this study, we describe a four-generation Han Chinese family with eight affected members. Haplotype analysis, Affymetrix SNP 6.0 arrays, qPCR, and gap-PCR were performed. Haplotyping results linked the disease-causing region to the 7q36 region that includes the zone of polarizing activity-regulatory sequence. A 442-kb duplication was found on chromosome 7 that co-segregated with the disease phenotype. The extent of the duplication was determined by qPCR, and the breakpoints were identified by gap-PCR and direct sequencing. This mutation was not detected in normal members in the same family. Our data therefore suggest that this novel microduplication, between 155,913,768 and 156,355,553 bp on chromosome 7, could be considered the cause of TPTPS in this kindred.