RESUMEN

OBJECTIVE: The purpose of this study was the clinical and pathological characterisation of a new autosomal dominant gastric polyposis syndrome, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). METHODS: Case series were examined, documenting GAPPS in three families from Australia, the USA and Canada. The affected families were identified through referral to centralised clinical genetics centres. RESULTS: The report identifies the clinical and pathological features of this syndrome, including the predominant dysplastic fundic gland polyp histology, the exclusive involvement of the gastric body and fundus, the apparent inverse association with current Helicobacter pylori infection and the autosomal dominant mode of inheritance. CONCLUSIONS: GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma. It is characterised by the autosomal dominant transmission of fundic gland polyposis, including areas of dysplasia or intestinal-type gastric adenocarcinoma, restricted to the proximal stomach, and with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

Asunto(s)

Adenocarcinoma/diagnóstico , Síndromes Neoplásicos Hereditarios/diagnóstico , Pólipos/diagnóstico , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/microbiología , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Niño , Femenino , Genes Dominantes , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/microbiología , Síndromes Neoplásicos Hereditarios/patología , Linaje , Pólipos/genética , Pólipos/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología

RESUMEN

A genetic counselor is often faced with the difficult task of conveying a set of complex and highly abstract factors associated with the client's risk of developing a familial disorder. The client is faced with the even more difficult task of making significant health-related decisions about an event which may or may not eventuate. Although there is a large corpus of research on this topic, much of the knowledge on risk communication is difficult to apply in a practical context. In this paper we draw together some insights on risk communication and decision-making under conditions of uncertainty, and apply them directly to the problem of communicating familial cancer risk. In particular, we focus on the distinction between individual risk and observed frequencies of adverse events, various framing effects, and contextualizing risk communication. We draw attention to some of the potential pitfalls in counseling about risk and offer avenues for circumventing them.

Asunto(s)

Comunicación , Asesoramiento Genético/métodos , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/psicología , Neoplasias/genética , Relaciones Profesional-Paciente , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/prevención & control , Neoplasias de la Mama/psicología , Femenino , Tamización de Portadores Genéticos , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/psicología , Humanos , Funciones de Verosimilitud , Neoplasias/prevención & control , Neoplasias/psicología , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Neoplasias Ováricas/psicología , Probabilidad , Pronóstico , Riesgo

RESUMEN

OBJECTIVE: To increase the awareness among at risk relatives of the availability of genetic testing for a familial disorder while respecting their autonomy and privacy. METHODS: This was a comparison of preintervention and postintervention cohorts of families carried out in a state wide clinical service providing genetic counselling and testing for people at risk of familial adult onset cancer. Unaffected relatives who were not clients of the service in 74 kindreds with familial mutations causing familial breast and ovarian cancer, hereditary non-polyposis colorectal cancer, or Cowden syndrome were included in the study. In the baseline cohort (41 kindreds), family members who were clients of the clinical service and had been shown to be carriers of mutations were asked to advise relatives that genetic testing was available. In the intervention cohort (33 kindreds), the clinical service obtained consent to advise at risk relatives by letter that genetic testing was available. The main outcome measures were: (a) proportion of unaffected first and second degree relatives of the proband in each family whose genetic status was clarified within 2 years of the mutation being identified in the family, and (b) concerns regarding privacy and autonomy voiced by relatives receiving these letters. RESULTS: In the baseline cohort, the average proportion of relatives in each family whose genetic status was clarified was 23%. In the intervention cohort, the average proportion of relatives in each family whose genetic status was clarified was 40% (p = 0.001). None of the relatives in the intervention cohort complained of a breach of privacy or autonomy. CONCLUSION: Clinical services can take an effective and proactive approach to notifying relatives who are not their clients of the availability of genetic testing without compromising principles of privacy and autonomy.

Asunto(s)

Ética Clínica , Salud de la Familia , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas/ética , Adolescente , Estudios de Cohortes , Correspondencia como Asunto , Humanos

RESUMEN

Cowden syndrome (OMIM No 158350) is a pleomorphic, autosomal dominant syndrome characterised by hamartomas in tissues derived from the endoderm, mesoderm, and ectoderm. It is caused by germline mutations in the PTEN gene and is allelic to the Bannayan-Riley-Ruvalcaba and Lhermitte-Duclos syndromes. The three syndromes are defined on clinical grounds but there is overlap in their definitions. The clinical features include trichilemmomas, verrucose lesions of the skin, macrocephaly, intellectual disability, cerebellar gangliocytoma, thyroid adenomas, fibroadenomas of the breast, and hamartomatous colonic polyps. Cutaneous haemangiomas are occasionally noted. Malignancies often arise in the affected tissues. Visceral arteriovenous malformations are a recognised component of the Bannayan-Riley-Ruvalcaba syndrome but have been reported rarely in Cowden syndrome. A family is described with a clinical diagnosis of Cowden syndrome, a familial frameshift mutation in the PTEN gene, and large visceral arteriovenous malformations. The association of these pleomorphic syndromes with arteriovenous malformations can be explained by the putative role of the PTEN gene in suppressing angiogenesis. Recognition of arteriovenous malformations as a clinical feature of Cowden syndrome has implications for the clinical management of patients with this disorder.

Asunto(s)

Malformaciones Arteriovenosas/diagnóstico , Síndrome de Hamartoma Múltiple/diagnóstico , Adulto , Malformaciones Arteriovenosas/diagnóstico por imagen , Malformaciones Arteriovenosas/genética , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Síndrome de Hamartoma Múltiple/genética , Humanos , Persona de Mediana Edad , Fosfohidrolasa PTEN/genética , Radiografía

RESUMEN

This multicentre study examined the influence of patient demographic, disease status and psychological variables on clinical geneticists/genetic counsellors (consultants) behaviours in initial consultations with women from high-risk breast cancer families. One hundred and fifty-eight women completed a pre-clinic self-report questionnaire. The consultations were audiotaped, transcribed verbatim and coded. Consultants did not vary their behaviour according to women's expectations. However, significantly more aspects of genetic testing were discussed with women who were affected with breast cancer (P<0.001), screening and management with unaffected women (P=0.01) and breast cancer prevention with younger women (P=0.01). Prophylactic mastectomy was discussed more frequently with women with medical and allied health training (P=0.02), and prophylactic oophorectomy with women affected with breast cancer (P=0.03), those in non-professional occupations (P=0.04) and with a family history of breast and ovarian cancer (P<0.001). Consultants used significantly more behaviours to facilitate understanding with women who were in non-professional occupations (P=0.04); facilitated active patient involvement more with women affected with breast cancer (P<0.001) and used more supportive and counselling behaviours with affected women (P=0.02). This study showed that patient demographics were more likely to predict consultants' communication behaviours than the woman's psychological status. Methods to facilitate assessment of psychological morbidity are needed to allow more tailored communication.

Asunto(s)

Neoplasias de la Mama/psicología , Comunicación , Asesoramiento Genético , Educación en Salud , Síndromes Neoplásicos Hereditarios/psicología , Grabación en Cinta , Mujeres/psicología , Adulto , Australia/epidemiología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/prevención & control , Análisis Mutacional de ADN , Emociones , Asesoramiento Genético/métodos , Asesoramiento Genético/psicología , Pruebas Genéticas/psicología , Humanos , Conocimiento , Mastectomía/psicología , Síndromes Neoplásicos Hereditarios/epidemiología , Síndromes Neoplásicos Hereditarios/genética , Ocupaciones , Ovariectomía , Aceptación de la Atención de Salud , Educación del Paciente como Asunto , Participación del Paciente , Riesgo , Muestreo , Encuestas y Cuestionarios

RESUMEN

We describe two children with a brain defect similar to that described as 'microlissencephaly', as defined in Barkovich et aL [(1998) Neuroped 29: 113-119]. Concomitant malformations (cardiac, spinal, urogenital) may represent components of a wider syndrome complex; alternatively, or additionally, there may have been a valproate teratogenic effect. The inheritance is likely to be autosomal recessive, although X-linkage cannot be excluded.

Asunto(s)

Anomalías Múltiples/patología , Encéfalo/anomalías , Cardiopatías Congénitas/patología , Columna Vertebral/anomalías , Anomalías Urogenitales/patología , Anomalías Inducidas por Medicamentos , Anomalías Múltiples/genética , Anticonvulsivantes/efectos adversos , Enfermedades Fetales/patología , Cardiopatías Congénitas/genética , Humanos , Lactante , Masculino , Microcefalia/genética , Microcefalia/patología , Linaje , Fenotipo , Anomalías Urogenitales/genética , Ácido Valproico/efectos adversos

RESUMEN

Opitz syndrome (OS) is a genetically heterogeneous malformation disorder. Patients with OS may present with a variable array of malformations that are indicative of a disturbance of the primary midline developmental field. Mutations in the C-terminal half of MID1, an RBCC (RING, B-box and coiled-coil) protein, have recently been shown to underlie the X-linked form of OS. Here we show that the MID1 gene spans at least 400 kb, almost twice the distance originally reported and has a minimum of six mRNA isoforms as a result of the alternative use of 5' untranslated exons. In addition, our detailed mutational analysis of MID1 in a cohort of 15 patients with OS has resulted in the identification of seven novel mutations, two of which disrupt the N-terminus of the protein. The most severe of these (E115X) is predicted to truncate the protein before the B-box motifs. In a separate patient, a missense change (L626P) was found that also represents the most C-terminal alteration reported to date. As noted with other C-terminal mutations, GFP fusion constructs demonstrated that the L626P mutant formed cytoplasmic clumps in contrast to the microtubular distribution seen with the wild-type sequence. Notably, however, both N-terminal mutants showed no evidence of cytoplasmic aggregation, inferring that this feature is not pathognomonic for X-linked OS. These new data and the finding of linkage to MID1 in the absence of a demonstrable open reading frame mutation in a further family support the conclusion that X-linked OS results from loss of function of MID1.

Asunto(s)

Anomalías Múltiples/genética , Ligamiento Genético , Proteínas de Microtúbulos , Mutación , Proteínas Nucleares , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Secuencias de Aminoácidos , Núcleo Celular/metabolismo , Codón sin Sentido , Citoplasma/metabolismo , ADN Complementario , Exones , Femenino , Humanos , Masculino , Microtúbulos/metabolismo , Mutación Missense , Sistemas de Lectura Abierta , Linaje , Proteínas Recombinantes de Fusión/metabolismo , Síndrome , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas , Cromosoma X , Dedos de Zinc

Asunto(s)

Craneosinostosis/genética , Pérdida Auditiva Sensorineural/genética , Mutación Puntual , Receptores de Factores de Crecimiento de Fibroblastos/genética , Craneosinostosis/complicaciones , Sordera/genética , Pérdida Auditiva Sensorineural/complicaciones , Humanos , Linaje

RESUMEN

Five autosomal dominant craniosynostosis syndromes (Apert, Crouzon, Pfeiffer, Jackson-Weiss and Crouzon syndrome with acanthosis nigricans) result from mutations in FGFR genes. Fourteen unrelated patients with FGFR2-related craniosynostosis syndromes were screened for mutations in exons IIIa and IIIc of FGFR2. Eight of the nine mutations found have been reported, but one patient with Pfeiffer syndrome was found to have a novel G-to-C splice site mutation at-1 relative to the start of exon IIIc. Of those mutations previously reported, the mutation C1205G was unusual in that it was found in two related patients, one with clinical features of Pfeiffer syndrome and the other having mild Crouzon syndrome. This degree of phenotypic variability shows that the clinical features associated with a specific mutation do not necessarily breed true.

Asunto(s)

Craneosinostosis/genética , Mutación , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Adulto , Craneosinostosis/enzimología , Femenino , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Síndrome

RESUMEN

A boy with brachycephaly without craniosynostosis, raised intracranial pressure, deafness, cataracts, and global developmental delay is described.

Asunto(s)

Catarata/congénito , Sordera/congénito , Cabeza/anomalías , Discapacidad Intelectual , Discapacidades del Desarrollo , Humanos , Recién Nacido , Masculino , Síndrome

RESUMEN

Autosomal recessive spinal muscular atrophy (SMA) has been mapped to a 6-cM interval on chromosome 5q12-13.3, flanked proximally by locus D5S6 and distally by locus D5S112. In this study we describe the isolation of two new microsatellite markers (EF1/2a and EF13/14) near locus D5S125, which lies 2 cM distal to D5S6. We show by linkage analysis and the study of the recombinants in 55 SMA pedigrees that the disease lies in the 4-cM interval between EF1/2a and D5S112. Fluorescence in situ analysis of cosmids from D5S6, EF1/2 and D5S112 confirms the genetic order and relative distance of markers. The microsatellites EF1/2a and EF13/14 are the first highly polymorphic PCR-based proximal markers in SMA to be described, and will be of value in prenatal prediction of the disorder.

Asunto(s)

Cromosomas Humanos Par 5 , ADN Satélite/genética , Diagnóstico Prenatal/métodos , Atrofias Musculares Espinales de la Infancia/diagnóstico , Atrofias Musculares Espinales de la Infancia/genética , Secuencia de Bases , Mapeo Cromosómico , Femenino , Enfermedades Fetales/diagnóstico , Enfermedades Fetales/genética , Ligamiento Genético , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Valor Predictivo de las Pruebas , Embarazo , Recombinación Genética

RESUMEN

Dystrophin-related protein (DRP or 'utrophin') is localized in normal adult muscle primarily at the neuromuscular junction. In the absence of dystrophin in Duchenne muscular dystrophy (DMD) patients, DRP is also present in the sarcolemma. DRP is expressed in fetal and regenerating muscle and may play a similar role to dystrophin in early development, although it remains to be determined whether DRP can functionally replace dystrophin in adult tissue. Previously we described a 3.5-kilobase complementary DNA clone that exhibits 80 per cent homology to the C-terminal domain of dystrophin. This sequence identifies a 13-kilobase transcript that maps to human chromosome 6 (refs 2, 11). Antibodies raised against the gene product identify a polypeptide with a relative molecular mass of about 400K in all tissues examined. To investigate the relationship between DRP and dystrophin in more detail, we have cloned and sequenced the whole DRP cDNA. Homology between DRP and dystrophin extends over their entire length, suggesting that they derive from a common ancestral gene. Comparative analysis of primary sequences highlights regions of functional importance, including those that may mediate the localization of DRP and dystrophin in the muscle cell.

Asunto(s)

Proteínas del Citoesqueleto/química , Proteínas de la Membrana , Actinina/química , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Pollos , Clonación Molecular , Codón , Secuencia de Consenso , ADN/química , ADN/genética , Distrofina/química , Glioma , Humanos , Ratones , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Homología de Secuencia de Aminoácido , Células Tumorales Cultivadas , Utrofina

RESUMEN

We have examined seven pedigrees that include individuals with a recently described X-linked form of severe mental retardation associated with alpha-thalassemia (ATR-X syndrome). Using hematologic and molecular approaches, we have shown that intellectually normal female carriers of this syndrome may be identified by the presence of rare cells containing HbH inclusions in their peripheral blood and by an extremely skewed pattern of X inactivation seen in cells from a variety of tissues. Linkage analysis has localized the ATR-X locus to an interval of approximately 11 cM between the loci DXS106 and DXYS1X (Xq12-q21.31), with a peak LOD score of 5.4 (recombination fraction of 0) at DXS72. These findings provide the basis for genetic counseling, assessment of carrier risk, and prenatal diagnosis of the ATR-X syndrome. Furthermore, they represent an important step in developing strategies to understand how the mutant ATR-X allele causes mental handicap, dysmorphism, and down-regulation of the alpha-globin genes.

Asunto(s)

Compensación de Dosificación (Genética) , Discapacidad Intelectual/genética , Cromosoma X , Talasemia alfa/genética , Femenino , Tamización de Portadores Genéticos , Ligamiento Genético , Marcadores Genéticos/genética , Globinas/genética , Humanos , Escala de Lod , Masculino , Linaje , Riesgo , Síndrome

Asunto(s)

Distrofia Miotónica/diagnóstico , Distrofia Miotónica/genética , Análisis Mutacional de ADN , Femenino , Genética de Población , Genotipo , Humanos , Recién Nacido , Biología Molecular , Distrofia Miotónica/congénito , Fenotipo , Embarazo , Secuencias Repetitivas de Ácidos Nucleicos

Asunto(s)

Enfermedades Neuromusculares/genética , Alelos , Variación Genética/genética , Humanos , Mutación/genética , Fenotipo

RESUMEN

Although autosomal recessive spinal muscular atrophy (SMA) has been mapped to chromosome 5q12-q13, there is for this region no genetic map based on highly informative markers. In this study we present the mapping of two previously reported microsatellite markers in 40 CEPH and 31 SMA pedigrees. We also describe the isolation of a new microsatellite marker at the D5S112 locus. The most likely order of markers (with recombination fractions given in parentheses) is 5cen-D5S6-(.02)-D5S125-(.04)-(JK53CA1/2,D5S11 2)-(.04)-D5S39-qter. The relative order of D5S6, D5S112, and D5S39 was confirmed by in situ hybridization. Multipoint linkage analysis in 31 SMA families indicates that the SMA locus lies in the 6-cM interval between D5S6 and JK53CA1/2, D5S112.

Asunto(s)

Mapeo Cromosómico/métodos , Cromosomas Humanos Par 5 , Atrofias Musculares Espinales de la Infancia/genética , Secuencia de Bases , Cromosomas Fúngicos , Clonación Molecular , ADN/análisis , ADN Satélite/análisis , Femenino , Ligamiento Genético/genética , Marcadores Genéticos , Humanos , Lactante , Escala de Lod , Masculino , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Linaje , Reacción en Cadena de la Polimerasa , Cromosoma X

RESUMEN

Spinal muscular atrophy (SMA) is a common cause of inherited morbidity and mortality in childhood. The wide range of phenotypes in SMA, uncertainty regarding its mode of inheritance, and the suggestion of linkage heterogeneity have complicated the genetic counselling of parents of affected children. The locus responsible for autosomal recessive SMA has been mapped to 5q11.2-q13.3. The most likely order of loci is cen-D5S6-(SMA,D5S125)-(JK53CA1/2,D5S112)-D5S3 9-qter, with highly polymorphic loci being identified at JK53CA1/2 and D5S39. We describe linkage studies with another highly polymorphic locus, D5S127, that is closely linked to D5S39. This genetic map can be used as the basis for genetic counselling in families with autosomal recessive SMA. Appropriate allowance can be made for sporadic cases owing to non-inherited causes and for linkage heterogeneity or misdiagnoses.

Asunto(s)

Cromosomas Humanos Par 5 , Polimorfismo de Longitud del Fragmento de Restricción , Diagnóstico Prenatal , Atrofias Musculares Espinales de la Infancia/genética , Secuencia de Bases , Femenino , Enfermedades Fetales/diagnóstico , Genes Recesivos/genética , Asesoramiento Genético , Ligamiento Genético/genética , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Linaje , Atrofias Musculares Espinales de la Infancia/diagnóstico

RESUMEN

A 10-point genetic linkage map of the region 16q12.1 to 16q22.1 has been constructed using the CEPH reference families. Four loci, MT, D16S10, D16S91, and D16S4, not previously localized on a multipoint linkage map, were incorporated on the map presented here. The order of loci was cen-D16S39-MT, D16S65-D16S10-FRA16B-D16S38, D16S4, D16S91, D16S46-D16S47-HP-qter. The interval between D16S10 and 4D16S38 is 3.1 cM in males and 2.3 cM in females, and contains FRA16B. The cloning strategy for FRA16B will now be based on YAC walking from D16S10 and D16S38. The location of FRA16B between D16S10 and D16S38 provides a physical reference point for the multipoint linkage map on the short arm of chromosome 16.

Asunto(s)

Mapeo Cromosómico , Cromosomas Humanos Par 16 , Ligamiento Genético/genética , Clonación Molecular , Femenino , Marcadores Genéticos/genética , Humanos , Masculino , Polimorfismo de Longitud del Fragmento de Restricción , Recombinación Genética/genética

RESUMEN

The fragile X syndrome locus, FRAXA, is located at Xq27. Until recently, few polymorphic loci had been genetically mapped close to FRAXA. This has been attributed to an increased frequency of recombination at Xq27, possibly associated with the fragile X mutation. In addition, the frequency of recombination around FRAXA has been reported to vary among fragile X families. These observations suggested that the genetic map at Xq27 in normal populations was different from that in fragile X populations and that the genetic map also varied within the fragile X population. Such variability would reduce the reliability of carrier risk estimates based on DNA studies in fragile X families. Five polymorphic loci have now been mapped to within 4 cM of FRAXA--DXS369, DXS297, DXS296, IDS, and DXS304. The frequency of recombination at Xq26-q28 was evaluated using data at these loci and at more distant loci from 112 families with the fragile X syndrome. Two-point and multipoint linkage analyses failed to detect any difference in the recombination fractions in fragile X versus normal families. Two-point and multipoint tests of linkage homogeneity failed to detect any evidence of linkage heterogeneity in the fragile X families. On the basis of this analysis, genetic maps derived from large samples of normal families and those derived from fragile X families are equally valid as the basis for calculating carrier risk estimates in a particular family.

Asunto(s)

Síndrome del Cromosoma X Frágil/genética , Ligamiento Genético , Marcadores Genéticos , Humanos , Masculino , Recombinación Genética , Programas Informáticos , Cromosoma X

RESUMEN

The fragile X syndrome is the most common cause of familial mental retardation and is characterized by a fragile site at the end of the long arm of the X chromosome. The unusual genetics and cytogenetics of this X-linked condition make genetic counseling difficult. DNA studies were of limited value in genetic counseling, because the nearest polymorphic DNA loci had recombination fractions of 12% or more with the fragile X mutation, FRAXA. Five polymorphic loci have recently been described in this region of the X chromosome. The positions of these loci in relation to FRAXA were defined in a genetic linkage study of 112 affected families. The five loci--DXS369, DXS297, DXS296, IDS, and DXS304--had recombination fractions of 4% or less with FRAXA. The closest locus, DXS296, was distal to FRAXA and had a recombination fraction of 2%. The polymorphisms at these loci can be detected in DNA enzymatically digested with a limited number of restriction endonucleases. A strategy for DNA studies which is based on three restriction endonucleases and on five probes will detect one or more of these polymorphisms in 94% of women. This strategy greatly increases the utility of DNA studies in providing genetic advice to families with the fragile X syndrome.

Asunto(s)

Mapeo Cromosómico , Sondas de ADN , ADN/análisis , Síndrome del Cromosoma X Frágil/diagnóstico , Cromosoma X , Ligamiento Genético , Humanos , Mutación , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Recombinación Genética