RESUMEN
Male infertility affects about 7% of the general male population. Balanced structural chromosomal rearrangements are observed in 0.4-1.4% of infertile males and are considered as a well-established cause of infertility. However, underlying pathophysiological mechanisms still need to be clarified. A strategy combining standard and high throughput cytogenetic and molecular technologies was applied in order to identify the candidate genes that might be implicated in the spermatogenesis defect in three male carriers of different balanced translocations. Fluorescence in situ hybridization (FISH) and whole-genome paired-end sequencing were used to characterize translocation breakpoints at the molecular level while exome sequencing was performed in order to exclude the presence of any molecular event independent from the chromosomal rearrangement in the patients. All translocation breakpoints were characterized in the three patients. We identified four variants: a position effect on LACTB2 gene in Patient 1, a heterozygous CTDP1 gene disruption in Patient 2, two single-nucleotide variations (SNVs) in DNAH5 gene and a heterozygous 17q12 deletion in Patient 3. The variants identified in this study need further validation to assess their roles in male infertility. This study shows that beside the mechanical effect of structural rearrangement on meiosis, breakpoints could result in additional alterations such as gene disruption or position effect. Moreover, additional SNVs or copy number variations may be fortuitously present and could explain the variable impact of chromosomal rearrangements on spermatogenesis. In conclusion, this study confirms the relevance of combining different cytogenetic and molecular techniques to investigate patients with spermatogenesis disorders and structural rearrangements on genomic scale.
Asunto(s)
Estudios de Asociación Genética/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Infertilidad Masculina/genética , Espermatogénesis/genética , Translocación Genética , Adulto , Astenozoospermia/genética , Dineínas Axonemales/genética , Secuencia de Bases , Puntos de Rotura del Cromosoma , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Fosfoproteínas Fosfatasas/genética , Polimorfismo de Nucleótido Simple , Secuenciación del Exoma , Secuenciación Completa del Genoma , beta-Lactamasas/genéticaRESUMEN
Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.
Asunto(s)
Discapacidad Intelectual/genética , Complejo Mediador/genética , Niño , Preescolar , Femenino , Humanos , Discapacidad Intelectual/diagnóstico , Masculino , Mutación Missense , FenotipoRESUMEN
Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.
Asunto(s)
Trastorno Autístico/genética , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 16/fisiología , Obesidad/genética , Adolescente , Adulto , Anciano , Trastorno del Espectro Autista/genética , Índice de Masa Corporal , Niño , Preescolar , Cromatina/metabolismo , Cromatina/fisiología , Deleción Cromosómica , Duplicación Cromosómica , Cromosomas Humanos Par 16/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Discapacidad Intelectual/genética , Masculino , Megalencefalia/genética , Microcefalia/genética , Persona de Mediana Edad , FenotipoRESUMEN
BACKGROUND: Today, sequencing is frequently carried out by Massive Parallel Sequencing (MPS) that cuts drastically sequencing time and expenses. Nevertheless, Sanger sequencing remains the main validation method to confirm the presence of variants. The analysis of MPS data involves the development of several bioinformatic tools, academic or commercial. We present here a statistical method to compare MPS pipelines and test it in a comparison between an academic (BWA-GATK) and a commercial pipeline (TMAP-NextGENe®), with and without reference to a gold standard (here, Sanger sequencing), on a panel of 41 genes in 43 epileptic patients. This method used the number of variants to fit log-linear models for pairwise agreements between pipelines. To assess the heterogeneity of the margins and the odds ratios of agreement, four log-linear models were used: a full model, a homogeneous-margin model, a model with single odds ratio for all patients, and a model with single intercept. Then a log-linear mixed model was fitted considering the biological variability as a random effect. RESULTS: Among the 390,339 base-pairs sequenced, TMAP-NextGENe® and BWA-GATK found, on average, 2253.49 and 1857.14 variants (single nucleotide variants and indels), respectively. Against the gold standard, the pipelines had similar sensitivities (63.47% vs. 63.42%) and close but significantly different specificities (99.57% vs. 99.65%; p < 0.001). Same-trend results were obtained when only single nucleotide variants were considered (99.98% specificity and 76.81% sensitivity for both pipelines). CONCLUSIONS: The method allows thus pipeline comparison and selection. It is generalizable to all types of MPS data and all pipelines.
Asunto(s)
Biología Computacional/métodos , Modelos Estadísticos , Epilepsia/genética , Epilepsia/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación INDEL , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADNRESUMEN
Left ventricular noncompaction cardiomyopathy (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. A NGS workflow, based on a panel of 95 genes developed for sequencing most prevalent sudden cardiac death-causing genes, was used to make a rapid and costless molecular diagnosis in two siblings with a severe noncompaction cardiomyopathy starting prenatally and leading to rapid cardiac failure. For the first time, a total homozygous PKP2 deletion was identified. This molecular defect was further confirmed by MLPA and array-comparative genomic hybridization (CGH). Heterozygous PKP2 mutations are usually reported in a significant proportion of Arrhythmogenic Right Ventricular Cardiomyopathy cases. Our results show, for the first time, the involvement of PKP2 in severe cardiomyopathy with ventricular non compaction.
Asunto(s)
Cardiomiopatías/genética , Eliminación de Gen , Predisposición Genética a la Enfermedad/genética , Placofilinas/genética , Cardiomiopatías/patología , Hibridación Genómica Comparativa/métodos , Consanguinidad , Salud de la Familia , Femenino , Ventrículos Cardíacos/anomalías , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Homocigoto , Humanos , Recién Nacido , Masculino , Linaje , HermanosRESUMEN
Kabuki syndrome (KS-OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with KS and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptive Reasoning Index (PRI), Processing Speed Index (PSI), and Working Memory Index (WMI). In addition, molecular data and several clinical symptoms were studied. FSIQ and VCI scores were 10 points lower for patients with a truncating mutation than other types of mutations. In addition, scores for FSIQ, VCI and PRI were lower for children with visual impairment than normal vision. We also identified a discrepancy in indexes characterized by high WMI and VCI and low PRI and PSI. We emphasize the importance of early identification and intensive care of visual disorders in patients with KS and recommend individual assessment of intellectual profile.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Estudios de Asociación Genética , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/genética , Mutación , Proteínas de Neoplasias/genética , Fenotipo , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/genética , Adolescente , Alelos , Niño , Análisis Mutacional de ADN , Femenino , Orden Génico , Sitios Genéticos , Humanos , Inteligencia , Masculino , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Genomic inversions are usually balanced, but unusual patterns have been described in haemophilia A (HA) patients for intron 22 (Inv22) and intron 1 (Inv1) inversions leading to the hypothesis of more complex rearrangements involving deletions or duplications. AIM: To characterize five abnormal patterns either in Southern blot and long-range PCR for Inv22 or in PCR for Inv1. MATERIALS AND METHODS: All patients were studied using cytogenetic microarray analysis (CMA). RESULTS: In all cases, CMA analysis found that each inversion was associated with complex Xq28 rearrangement. In three patients, CMA analysis showed large duplication ranging from 230 to 1302 kb and encompassing a various number of contiguous genes among which RAB39B. RAB39B duplication is a strong candidate gene for X-linked intellectual disability (XLID). Surprisingly, none of the severe HA patients with RAB39B duplication reported in this study or in the literature exhibited XLID. We hypothesise that F8 complex rearrangement down regulated RAB39B expression. In the two remaining patients, CMA analysis found Xq28 large deletion (from 285 to 522 kb). Moyamoya syndrome was strongly suspected in one of them who carried BRCC3 deletion. CONCLUSION: Because several F8 neighbouring genes are associated with other pathologies such as XLID and cardiovascular disease, all HA patients where complex Xq28 rearrangement was suspected should be referred to a geneticist for possible utility of a pangenomic study. Such investigation should be carefully considered in genetic counselling in female carriers to assess the risk of transmitting severe HA with a "contiguous gene syndrome".
Asunto(s)
Análisis Citogenético , Factor VIII/genética , Reordenamiento Génico , Asesoramiento Genético , Hemofilia A/genética , Femenino , Hemofilia A/diagnóstico , Humanos , Intrones/genética , Masculino , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.
Asunto(s)
Exoma/genética , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Secuencia Conservada , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Mutación/genética , Embarazo , Análisis de Secuencia de ADN , SíndromeRESUMEN
Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.
Asunto(s)
Anomalías Múltiples/genética , Cardiomiopatías/genética , Enanismo/genética , Retardo del Crecimiento Fetal/genética , Síndromes de Inmunodeficiencia/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Microcefalia/genética , Osteocondrodisplasias/genética , ARN Nuclear Pequeño/genética , Enfermedades de la Retina/genética , Anomalías Múltiples/fisiopatología , Alelos , Cardiomiopatías/fisiopatología , Niño , Preescolar , Enanismo/fisiopatología , Femenino , Retardo del Crecimiento Fetal/fisiopatología , Feto , Humanos , Síndromes de Inmunodeficiencia/fisiopatología , Lactante , Recién Nacido , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Microcefalia/fisiopatología , Mutación , Osteocondrodisplasias/fisiopatología , Fenotipo , Enfermedades de Inmunodeficiencia Primaria , Enfermedades de la Retina/fisiopatología , Empalmosomas/genéticaRESUMEN
Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.
Asunto(s)
Hibridación Genómica Comparativa/métodos , Asesoramiento Genético/ética , Asesoramiento Genético/métodos , Hallazgos Incidentales , Revelación/ética , Femenino , Francia , Genes Dominantes/genética , Genes Recesivos/genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Masculino , Análisis por Micromatrices/métodos , Relaciones Médico-Paciente/ética , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 16/genética , Obesidad/genética , Obesidad/fisiopatología , Penetrancia , Adolescente , Adulto , Edad de Inicio , Envejecimiento , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/genética , Estudios de Cohortes , Europa (Continente) , Femenino , Estudio de Asociación del Genoma Completo , Heterocigoto , Humanos , Patrón de Herencia/genética , Masculino , Mutación/genética , Obesidad/complicaciones , Reproducibilidad de los Resultados , Caracteres Sexuales , Adulto JovenRESUMEN
Array comparative genomic hybridization (aCGH) has progressively replaced conventional karyotype in the diagnostic strategy of intellectual disability (ID) and congenital malformations. This technique increases not only the diagnostic rate but also the possibility of finding unexpected variants unrelated to the indication of referral, namely incidental findings. The incidental finding of copy number variants (CNVs) located in X-linked genes in girls addresses the crucial question of genetic counseling in the family. We report here five cases of CNVs involving the dystrophin gene detected by aCGH in girls referred for developmental delay, without any family history of dystrophinopathy. The rearrangements included three in-frame deletions; one maternally and two paternally inherited, and two frameshift duplications: one de novo and one from undetermined inheritance. In two cases, the deletion identified in a girl was transmitted by the asymptomatic father. In the case of the maternally inherited deletion, prenatal diagnosis of dystrophinopathy was proposed for an ongoing pregnancy, whereas the cause of developmental delay in the index case remained unknown. Through these cases, we discussed the challenges of genetic counseling in the family, regarding the predictive issues for male individuals at risk for a muscular dystrophy without precise knowledge of the clinical consequences of some CNVs in the DMD gene.
Asunto(s)
Hibridación Genómica Comparativa , Heterocigoto , Hallazgos Incidentales , Preescolar , Variaciones en el Número de Copia de ADN , Distrofina/genética , Familia , Femenino , Asesoramiento Genético , Humanos , Lactante , Distrofias Musculares/diagnóstico , Distrofias Musculares/genéticaRESUMEN
Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval (CI), 0.042-0.082]. Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array-CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context.
Asunto(s)
Aberraciones Cromosómicas , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pronóstico , Adulto , Hibridación Genómica Comparativa , Femenino , Francia , Estudios de Asociación Genética , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Hibridación Fluorescente in Situ , Cariotipo , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Embarazo , Diagnóstico Prenatal , Estudios Prospectivos , Riesgo , Suiza , Adulto JovenAsunto(s)
Algoritmos , Diagnóstico Prenatal , Trisomía , Secuenciación Completa del Genoma , Femenino , Humanos , EmbarazoRESUMEN
We report on the cytogenetic and molecular characterization of a constitutional de novo ring chromosome 22 (r(22)) in 2 unrelated patients with emphasis on different hypotheses proposed to explain the phenotypic variability characterizing this genomic disorder. In both patients, molecular investigations using FISH and array-CGH techniques revealed a 22q terminal deletion involving the 22q13.33 critical region. The size of the deletion was estimated to at least 1.35 Mb in the first proband and to only 300 kb in the second. They both exhibited the major features of r(22) syndrome, but the first patient was more profoundly affected. He had a more severe phenotype, further complicated by behavioral anomalies, autistic-like features with abnormal EEG pattern and brain MRI profile. Haploinsufficiency of the SHANK3 gene, lying in the minimal critical region, is nowadays considered as responsible for most neurobehavioral anomalies. Nevertheless, phenotypic severity and occurrence of additional features in the first patient suggest a potential involvement of one or more specific gene(s) located proximally to SHANK3 (as PLXNB2, PANX2, ALG12 or MLC1), acting either independently of it or by regulating or promoting its expression and thus disrupting its function when deleted.
Asunto(s)
Deleción Cromosómica , Discapacidad Intelectual/genética , Cariotipo Anormal , Secuencia de Bases , Encéfalo/diagnóstico por imagen , Proteínas de Ciclo Celular/genética , Trastornos de la Conducta Infantil/genética , Preescolar , Cromosomas Humanos Par 22/genética , Hibridación Genómica Comparativa , Femenino , Haploinsuficiencia , Chaperonas de Histonas/genética , Humanos , Masculino , Metafase , Proteínas del Tejido Nervioso/genética , Fenotipo , Radiografía , Cromosomas en Anillo , Factores de Transcripción/genéticaRESUMEN
We led a clinical and molecular characterization of a patient with mild mental delay and dysmorphic features initially referred for cytogenetic exploration of an azoospermia. We employed FISH and array CGH techniques for a better definition and refinement of a double chromosome aberration associating a 17p microdeletion with partial monosomy 21q due to 1:3 meiotic segregation of a maternal reciprocal translocation t(17;21)(p13.3;q21.2) revealed after banding analysis. Brain MRI depicted partial callosal and mild diffuse cerebral atrophies, but without expected signs of lissencephaly. The patient's karyotype formula was: 45,XY,der(17)t(17;21)(p13.3;q21.2)mat,-21. FISH study confirmed these rearrangements and array CGH analysis estimated the loss sizes to at least 635 kb on chromosome 17 and to 15.6 Mb on chromosome 21. The absence of lissencephaly and major brain malformations often associated with 17p terminal deletions could be attributed to the retention of PAFAH1B1, YWHAE and CRK genes. Dysmorphic features, moderate mental impairment and minor brain malformations could result from the 21q monosomy and particularly the partial deletion of the APP-SOD1 region. Azoospermia should result from gamete apoptosis induced by a control mechanism triggered in response to chromosome imbalances. Our study provides an additional case for better understanding and delineating both 17p and 21q deletions.
Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 21/genética , Anomalías Múltiples/patología , Adulto , Atrofia , Encéfalo/patología , Cromosomas Humanos Par 13/genética , Anomalías Craneofaciales/patología , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/patología , Cariotipificación , Masculino , Translocación GenéticaRESUMEN
BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.
Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 4/genética , Trastornos del Crecimiento/patología , Discapacidad Intelectual/patología , Trastornos del Desarrollo del Lenguaje/patología , Anomalías Múltiples/patología , Adolescente , Niño , Preescolar , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Síndrome , Adulto JovenRESUMEN
The increasing use of array-comparative genomic hybridization (array-CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4-BP5 microdeletion out of a series of 4625 patients screened by array-CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical approximately 1.5 Mb BP4-BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Adolescente , Emparejamiento Base/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Heterocigoto , Humanos , Patrón de Herencia/genética , Masculino , Linaje , FenotipoRESUMEN
This article focuses on six questions raised by genetic testing in human: (1) the use of genetic tests, (2) information given to relatives of patients affected with genetic disorders, (3) prenatal and preimplantatory diagnosis for late onset genetic diseases and the use of pangenomic tests in prenatal diagnosis, (4) direct-to-consumer genetic testing, (5) population screening in the age of genomic medicine and (6) incidental findings when genetic testing are used.