RESUMEN
BACKGROUND: IGF1R (insulin-like growth factor 1 receptor) haploinsufficiency is a rare event causing difficulties in defining clear genotype-phenotype correlations, although short stature is its well established hallmark. Several pure 15q26 monosomies (n=22) have been described in the literature, including those with breakpoints proximal to the IGF1R gene. Clinical heterogeneity is characteristic for these mainly de novo telomeric deletions and is illustrated by the involvement of several different organ systems such as the heart, diaphragm, lungs, kidneys and limbs, besides growth failure in the patient's phenotype. The clinical variability in these patients could be explained by the haploinsufficiency of multiple genes besides the IGF1R gene. In comparison, the six different IGF1R mutations revealed to date exhibit some variance in their clinical features as well, probably because different parts of the downstream IGF1R signalling cascade were affected. METHODS AND RESULTS: Using the recently developed technique multiplex ligation dependent probe amplification (MLPA), a chromosome 15q26.3 microdeletion harbouring part of the IGF1R gene was identified in a Dutch family. This deletion segregated with short height in seven out of 14 relatives across three generations. Metaphase fluorescence in situ hybridisation (FISH) and Affymetrix 250k single nucleotide polymorphism (SNP) microarray were used to characterise the deletion into more detail and showed that exons 11-21 of the IGF1R and a small hypothetical protein (LOC 145814) were deleted. CONCLUSION: Clinical work-up of this newly identified family, which constitutes the smallest (0.095 Mb) pure 15q26.3 interstitial deletion to date, confirms that disruption of the IGF1R gene does not induce major organ malformation or severe mental retardation.
Asunto(s)
Fenotipo , Receptor IGF Tipo 1/genética , Eliminación de Secuencia/fisiología , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 15 , Estudios de Cohortes , Cara/patología , Femenino , Dedos/patología , Humanos , Hibridación Fluorescente in Situ , Masculino , Técnicas de Amplificación de Ácido Nucleico , Linaje , SíndromeRESUMEN
The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more hemangioblastomas or a single hemangioblastoma in combination with a typical visceral lesion. To evaluate this definition, we studied the frequency of germline VHL mutation in three patients groups: (i) multi-organ involvement (classic VHL), (ii) limited VHL manifestations meeting criteria (non-classic VHL) and (iii) patients with VHL-associated tumors not meeting current diagnostic VHL criteria. In addition, we validated multiplex ligation-dependent probe amplification (MLPA) as a rapid and reliable quantitative method for the identification of germline VHL deletions. The frequency of germline VHL mutations was very high in classic VHL cases with multi-organ involvement (95%), lower in non-classic cases that meet current diagnostic criteria but have limited VHL manifestations or single-organ involvement (24%) and low (3.3%), but tangible in cases not meeting current diagnostic VHL criteria. The detection of germline VHL mutations in patients or families with limited VHL manifestations, or single-organ involvement is relevant for follow-up of probands and early identification of at-risk relatives.
Asunto(s)
Frecuencia de los Genes , Mutación de Línea Germinal , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/genética , Southern Blotting , Análisis Mutacional de ADN , Humanos , Técnicas de Amplificación de Ácido Nucleico , Linaje , Prevalencia , Análisis de Secuencia de ADNRESUMEN
Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25-30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 (CYLN2) and general transcription factors (GTF2I and GTF2IRD1) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients. Recent studies of patients with partial deletions indicate that hemizygosity of GTF2I probably contributes to mental retardation in WS. Here we investigate whether CYLN2 and GTF2IRD1 contribute to the motoric and cognitive deficits in WS. Behavioral assessment of a new patient in which STX1A and LIMK1, but not CYLN2 and GTF2IRD1, are deleted showed that his cognitive and motor coordination functions were significantly better than in typical WS patients. Comparative analyses of gene specific CYLN2 and GTF2IRD1 knockout mice showed that a reduced size of the corpus callosum as well as deficits in motor coordination and hippocampal memory formation may be attributed to a deletion of CYLN2, while increased ventricle volume can be attributed to both CYLN2 and GTF2IRD1. We conclude that the motor and cognitive deficits in Williams Syndrome are caused by a variety of genes and that heterozygous deletion of CYLN2 is one of the major causes responsible for such dysfunctions.
Asunto(s)
Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/fisiología , Proteínas Musculares/genética , Proteínas Musculares/fisiología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Transactivadores/genética , Transactivadores/fisiología , Síndrome de Williams/patología , Síndrome de Williams/psicología , Animales , Cognición/fisiología , Condicionamiento Operante/fisiología , ADN/genética , Movimientos Oculares/fisiología , Miedo/psicología , Hibridación Fluorescente in Situ , Pruebas de Inteligencia , Imagen por Resonancia Magnética , Ratones , Ratones Noqueados , Actividad Motora/fisiología , Pruebas Neuropsicológicas , Equilibrio Postural/fisiología , Desempeño Psicomotor/fisiología , Síndrome de Williams/genéticaRESUMEN
OBJECTIVE: Screening for an increased number of chromosomes may improve the detection of abnormal embryos and thus contribute to the capability of preimplantation genetic screening (PGS) to detect the embryo(s) for transfer in IVF with the best chance for a healthy child. Good-quality day 4 and 5 embryos were analyzed after cryopreservation for the nine chromosomes mostly recommended for screening (13, 14, 15, 16, 18, 21, 22, X and Y), next to six additional chromosomes which are less well studied in this context (1, 2, 7, 6, 10 and 17). METHOD: The copy numbers of 15 chromosomes were investigated by fluorescence in situ hybridization (FISH) in three consecutive rounds. The proportion of aneuploid and mosaic embryos was determined and compared in retrospect to results in case only the recommended probe set had been analyzed. RESULTS: A total of 52 embryos from 29 infertile women were analyzed. Screening the embryos for six additional chromosomes increased the proportion of abnormal embryos from 67 to 81% (P = 0.03), owing to an increase in mosaic embryos. CONCLUSION: All but one of the meiotic aneuploidies found in this study would have been detected by the probe set most frequently used in PGS clinics. However, aneuploid cell lines originating from mitotic errors could be detected for almost all chromosomes, so screening of six additional chromosomes mainly increased the proportion of mosaic embryos. The added value of screening for six additional chromosomes in PGS for clinical practice will remain undetermined as long as the fate of mosaic embryos after transfer is unclear.
Asunto(s)
Aneuploidia , Trastornos de los Cromosomas/diagnóstico , Cromosomas/genética , Hibridación Fluorescente in Situ/métodos , Diagnóstico Preimplantación , Criopreservación , Femenino , Pruebas Genéticas , Humanos , Mosaicismo/embriología , EmbarazoRESUMEN
Congenital diaphragmatic hernia (CDH) is a relatively common birth defect with a high mortality. Although little is known about its etiology, there is increasing evidence for a strong genetic contribution. Both numerical and structural chromosomal abnormalities have been described in patients with CDH. Partial trisomy 11q and partial trisomy 22 associated with the common t(11;22) has been reported in several cases of CDH. It has been assumed that the diaphragmatic defect seen in these individuals was primarily due to duplication of material from chromosome 22q11. However, in this report we describe a family with a t(11;12) in which one of two brothers with partial trisomy 11q has a left sided posterolateral CDH. This is the second case of CDH in partial trisomy 11q due to an unbalanced translocation other than t(11;22). Using array-based comparative genomic hybridization and fluorescent in situ hybridization, we mapped the breakpoints in both brothers and their mother who is a balanced translocation carrier. Our results suggest that duplication of one or more genes on a approximately 19 Mb region of 11q23.3-qter predisposes to the development of CDH. These effects may be the primary cause of CDH in individuals t(11;22) or may be additive to effects from the duplication of chromosome 22 material. We also conclude that the partial trisomy 11q syndrome has a variable phenotype and that CDH should be added to the spectrum of anomalies that can be present in this syndrome.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 11/genética , Hernia Diafragmática/genética , Hernias Diafragmáticas Congénitas , Adulto , Preescolar , Cromosomas Humanos Par 12/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Masculino , Linaje , Fenotipo , Embarazo , Translocación Genética , TrisomíaRESUMEN
Congenital diaphragmatic hernia (CDH) has an incidence of 1 in 3,000 births and a high mortality rate (33%-58%). Multifactorial inheritance, teratogenic agents, and genetic abnormalities have all been suggested as possible etiologic factors. To define candidate regions for CDH, we analyzed cytogenetic data collected on 200 CDH cases, of which 7% and 5% showed numerical and structural abnormalities, respectively. This study focused on the most frequent structural anomaly found: a deletion on chromosome 15q. We analyzed material from three of our patients and from four previously published patients with CDH and a 15q deletion. By using array-based comparative genomic hybridization and fluorescent in situ hybridization to determine the boundaries of the deletions and by including data from two individuals with terminal 15q deletions but without CDH, we were able to exclude a substantial portion of the telomeric region from the genetic etiology of this disorder. Moreover, one patient with CDH harbored a small interstitial deletion. Together, these findings allowed us to define a minimal deletion region of approximately 5 Mb at chromosome 15q26.1-26.2. The region contains four known genes, of which two--NR2F2 and CHD2--are particularly intriguing gene candidates for CDH.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 15 , Hernia Diafragmática/genética , Hernias Diafragmáticas Congénitas , Anomalías Múltiples/genética , Humanos , Hibridación Fluorescente in Situ , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
In this article, we describe a large five-generation family with characteristics of the Saethre-Chotzen syndrome as well as of the blepharophimosis ptosis epicanthus inversus syndrome. Segregating with their phenotype is a deletion of the chromosome 7p21 TWIST gene locus. The TWIST gene indeed is involved in Saethre-Chotzen syndrome, a craniosynostosis syndrome further characterized by specific facial and limb abnormalities. However, only two members of our family exhibited craniosynostosis. This report demonstrates that the genetics of craniofacial anomalies are less straightforward than they sometimes appear to be. Not only craniosynostosis, but also subtle facial deformities could be indicative of an abnormality of the TWIST gene. In conclusion, the clinical spectrum of genetic abnormalities of the TWIST gene is highly variable. We therefore recommend that genetic analysis of the TWIST gene locus, including fluorescence in situ hybridization, should be considered in familial cases of facial and eyelid abnormalities without the presence of craniosynostosis.
Asunto(s)
Acrocefalosindactilia/genética , Eliminación de Gen , Proteínas Nucleares/genética , Factores de Transcripción/genética , Acrocefalosindactilia/patología , Oído/anomalías , Anomalías del Ojo/genética , Composición Familiar , Humanos , Cariotipificación , Linaje , Proteína 1 Relacionada con TwistAsunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 1/genética , Retardo del Crecimiento Fetal/genética , Trisomía/genética , Adulto , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Cariotipificación , Masculino , Fenotipo , Síndrome , Disomía Uniparental/genéticaRESUMEN
In five families with questionable chromosome rearrangements, we identified an interchromosomal insertion by fluorescent in situ hybridization (FISH). In case 1 with a dir ins (5;11)(p14;q14q24) in three generations, the mentally retarded and microcephalic proband showed a 5p14-->pter deletion. In case 2, a duplication (13)(q21.31--> q31.2) combined with a deletion (11)(q14-->q22) segregated from a reciprocal ins(11;13)(q14q122)(q21.32q31.2), causing a mixed phenotype with psychomotor retardation, caput quadratum, choanal atresia, and pes equinovarus. In case 3, a dir ins (18;5)(q21.3;p13.1p14) was associated with spontaneous abortions, in case 4, the proband with mental retardation, microcephaly, and a heart defect showed a pure trisomy of (12)(q13-->q15), which had segregated from a carrier of an ins (18;12)(p11.3;q13q15). In case 5, a duplication of (10)(q26.3-->q25.2) segregated from an inv ins(5;10)(q15;q26.3q25.2), which was passed on directly from a mother to her son,with mental retardation. In all families the elucidation of the insertional translocation (IT) considerably increased the associated genetic risks of carriers. For the review, we collected data from 81 articles on 87 IT probands on ascertainment, origin, familial transmittance, progeny, and genetic risks of IT carriers. We also discussed the recombinant chromosomes and complex rearrangements associated with ITs, and listed chromosome regions occurring solely as deletions, or solely as duplications, or as both to facilitate genotype/phenotype correlations. We conclude that ITs are rare chromosomal rearrangements with an 1:80,000 incidence, of which nearly 80% were referred because of congenital abnormalities and mental retardation. A maternal origin was seen in 59.5%, a paternal origin in 26.6%, and 13.9% were de novo. No notable difference in fertility between male and female IT carriers was noticed. Bias of ascertainment was excluded in 15 familial cases and led to an estimate of the genetic risks for IT carriers of 32.0-36.0%. The mean size of the inserted regions occurring solely as duplications (n=39) measures 0.96% of the haploid autosomal length (HAL), and of regions solely occurring as deletions (n=14) 0.47% HAL. In the families where both aneusomies occurred, the size of the insertions ranged between 0.22 and 1.21% HAL. Overall, the findings fit with the general idea that a surplus of genetic material is tolerated more easily than a deficiency.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Cromosomas Humanos , Elementos Transponibles de ADN , Aborto Espontáneo , Adulto , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Linaje , Embarazo , Eliminación de Secuencia , Translocación GenéticaRESUMEN
Fluorescent in situ Hybridization (FISH) was carried out for three cases of abnormal karyotypes in prenatal studies. Two concerned de novo structural anomalies and the third a marker chromosome. The origin of the extra material could be defined in all three cases, which gives a better insight into the relationship between genotype and phenotype and makes more adequate genetic counselling possible.
Asunto(s)
Aberraciones Cromosómicas/diagnóstico , Enfermedades Fetales/diagnóstico , Hibridación Fluorescente in Situ/métodos , Diagnóstico Prenatal/métodos , Adulto , Amniocentesis , Aberraciones Cromosómicas/genética , Bandeo Cromosómico , Trastornos de los Cromosomas , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 15 , Cromosomas Humanos Par 18 , Sondas de ADN , Síndrome de Dandy-Walker/diagnóstico , Síndrome de Dandy-Walker/genética , Femenino , Enfermedades Fetales/genética , Humanos , Recién Nacido , Cariotipificación , Embarazo , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Translocación Genética , TrisomíaRESUMEN
DNA markers YNZ22.1, YNH37.3, 144D6, and VAW508 were studied in five patients with the Miller-Dieker syndrome, 17 patients with the isolated lissencephaly sequence, one patient with a non-classified lissencephaly, and nine patients with an atypical cortical dysplasia. All patients had normal chromosomes except for a deletion 17p13.3 in one of the five Miller-Dieker patients. The five Miller-Dieker patients showed deletions of markers YNZ22.1 and YNH37.3 in contrast to the other patients tested. In one patient, the deletion was in the maternally contributed chromosome. Prenatal diagnosis by DNA analysis allowed exclusion of the recurrence of Miller-Dieker syndrome in a subsequent pregnancy.