Familial interstitial deletion of chromosome 4 (p15.2p16.1)

Interstitial deletion of the proximal short arm of chromosome 4, extending from p14 to p16.1 region, results in a distinct clinical syndrome. This proximal 4p deletion syndrome is characterized by variable degrees of mental retardation, unusual facies and minor dysmorphic features. Majority of the patients also show a tall, ectomorphic habitus and normal to excessive linear growth with age. While there have been several cases of such interstitial del(4p) cases reported, familial transmission of this condition has not been documented in the literature. This is the first report of a familial transmission of proximal del(4p) from a mother to her daughter, with both patients showing similar features. This report of the familial transmission of del(4p) has wider implications in genetic counseling.     

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q

Pyoderma gangrenosum, cystic acne, and aseptic arthritis are clinically distinct disorders within the broad class of inflammatory diseases. Although this triad of symptoms is rarely observed in a single patient, a three-generation kindred with autosomal-dominant transmission of these three disorders has been reported as "PAPA syndrome" (MIM 604416). We report mapping of a disease locus for familial pyoderma gangrenosum-acne-arthritis to the long arm of chromosome 15 (maximum two-point LOD score, 5.83; recombination fraction [straight theta] 0 at locus D15S206). Under the assumption of complete penetrance, haplotype analysis of recombination events defined a disease interval of 10 cM, between D15S1023 and D15S979. Successful identification of a single disease locus for this syndrome suggests that these clinically distinct disorders may share a genetic etiology. These data further indicate the role of genes outside the major histocompatibility locus in inflammatory disease.     

Familial congenital esophageal atresia

Summary Esophageal atresia with or without tracheoesophageal fistula (EA±TEF) usually occurs sporadically either as an isolated malformation or in conjunction with other congenital anomalies. Seventy-six familial cases are recorded in the literature. Two personal cases are additionally reported. An overview of the 33 pedigrees with familial occurence of EA is presented. All available data of relevance for genetic analysis are compiled in eight tables. Attention is given to possible heterogeneity between sporadic and familial and between isolated and associated EA. Guidelines for genetic counseling are presented. With exception of the cases where EA is part of a chromosomal or of a known monogenic or teratogenic syndrome, the recurrence risks fit into a multifactorial scheme.     

SRY-negative true hermaphrodites and an XX male in two generations of the same family

Two 46,XX true hermaphrodites and one XX male without genital ambiguities are reported. They coexist in two generations of the same pedigree, with paternal transmission and in the absence of SRY (sex-determining region, Y chromosome). These familial cases provide evidence to support the hypothesis that these disorders are alternative manifestations of the same genetic defect, probably an autosomal dominant mutation (with incomplete penetrance) or an X-linked mutation (limited by the presence of the Y chromosome).     

Absence of linkage between Alzheimer's disease and the HLA system

The study of a family in which multiple cases of Alzheimer's disease occurred in several generations offers the opportunity to test the genetic transmission of this disease. The HLA grouping of the members of a pedigree containing 10 affected members allowed to demonstrate that the disease is not due to a single dominant gene linked to the major histocompatibility complex. Although a more complex involvement of the major histocompatibility complex cannot be totally ruled out it is obvious that a strong linkage does not exist between Alzheimer's disease and HLA.     

Genetic study of spinocerebellar hereditary degenerations in Tunisia. Role of consanguinity in their occurrence

The genetic analysis of 101 genealogical trees of families with spinocerebellar heredo-degeneration enabled the authors to specify the transmission inheritance for each clinical type. Autosomic recessive transmission has been observed for Friedreich's ataxia (68 out of 69 families), Pierre-Marie's heredo-ataxia (15 families) and familial spastic paraplegia (2 families). A dominant mode of transmission has been observed in 13 families affected by familial spastic paraplegia (Strumpell-Lorrain) and in only one family with Friedreich's ataxia (an intermediate or incomplete form). It has also been observed that the consanguinity rate among this group of families is very high compared with that of the general tunisian population (25%). Marriage between cousins occurs in 75% of the cases of Friedreich's ataxia, in 78% of the cases of Pierre-Marie's heredo-ataxia and in only 61% of familial spastic paraplegia of Strumpell-Lorrain. The authors have come to the conclusion that the recessive autosomic transmission of the spino-cerebellar heredo-degenerative diseases are closely related to a high consanguinity rate.     

Inferior Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation in Purebred Eurasier Dogs with Familial Non-Progressive Ataxia: A Retrospective and Prospective Clinical Cohort Study

Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5 – 6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance.     

Evidence for a dominant major gene conferring predisposition to hepatitis C virus infection in endemic conditions

Hepatitis C virus (HCV), infecting 170 million people worldwide, is a major public health problem. In developing countries, unsafe injections and blood transfusions are thought to be the major routes of transmission. However, our previous work in a population from Egypt, endemic for HCV, revealed highly significant familial correlations, strongly suggesting the existence of both familial transmission of the virus and genetic predisposition to HCV infection. We investigated the hypothesis of genetic predisposition by carrying out a segregation analysis of HCV infection in the same population. We used a logistic regression model simultaneously taking into account a major gene effect, familial correlations and relevant risk factors. We analyzed 312 pedigrees (3,703 subjects). Overall HCV seroprevalence was 11.8% and increased with age. The main associated risk factors were previous parenteral treatment for schistosomiasis and blood transfusions. We found strong evidence for a dominant major gene conferring a predisposition to HCV infection. The frequency of the predisposing allele was 0.013, reflecting a strong predisposition to HCV infection in 2.6% of the subjects, particularly those under the age of 20. This study provides evidence for the involvement of host genetic factors in susceptibility/resistance to HCV infection in endemic conditions.     

Familial Fibrocystic Pulmonary Dysplasia: Observations in One Family

At least 31 cases of familial fibrocystic pulmonary dysplasia, within 10 families, have been described in the world literature. The mode of genetic transmission of this disease, however, has been uncertain until now. The author observed three unequivocal and five probable cases of familial fibrocystic pulmonary dysplasia among 56 members of one family. Diagnostic criteria included progressive dyspnea and cyanosis, digital clubbing, pulmonary hypertension, negative sweat tests, polycythemia, arterial hypoxia and hypocapnia, chest radiographs showing diffuse bilateral pulmonary fibrosis, and diffuse fibrocystic pulmonary dysplasia at postmortem examination (two cases). Among the three unequivocal cases one father-to-son transmission was observed. Non-sex-linked dominant transmission of familial fibrocystic pulmonary dysplasia is thereby proved for the first time. One patient also developed a bronchial carcinoma in addition to fibrocystic pulmonary dysplasia; this is considered to be a cause-and-effect relationship and not a coincidental complication.     

Precocious puberty: growth and genetics

The precise neuroendocrine mechanisms underlying activation of hypothalamic-pituitary-gonadal (HPG) axis maturation are elusive. The wide age range of pubertal onset among normal individuals throughout the world may suggest that both genetic and environmental factors modulate the timing of puberty. Early activation of the HPG axis, termed central precocious puberty (CPP), causes psychosocial difficulties and may lead to compromised final height, especially if medical intervention is delayed. Although CPP is considered to be idiopathic in the majority of patients, we have recently reported a 27.5% prevalence of familial cases among 147 patients with idiopathic CPP. Segregation analysis of this cohort suggested an autosomal dominant transmission with incomplete sex-dependent penetrance. Allelic variants of candidate genes that regulate the timing of puberty may cause familial CPP. Detection of these genes will provide a tool for identification of children at risk of developing CPP, enabling early intervention with the aim of preventing its distressing outcomes.     

Sirenomelia Phenotype in Bmp7;Shh Compound Mutants: A Novel Experimental Model for Studies of Caudal Body Malformations

Sirenomelia is a severe congenital malformation of the lower body characterized by the fusion of the legs into a single lower limb. This striking external phenotype consistently associates severe visceral abnormalities, most commonly of the kidneys, intestine, and genitalia that generally make the condition lethal. Although the causes of sirenomelia remain unknown, clinical studies have yielded two major hypotheses: i) a primary defect in the generation of caudal mesoderm, ii) a primary vascular defect that leaves the caudal part of the embryo hypoperfused. Interestingly, Sirenomelia has been shown to have a genetic basis in mice, and although it has been considered a sporadic condition in humans, recently some possible familial cases have been reported. Here, we report that the removal of one or both functional alleles of Shh from the Bmp7-null background leads to a sirenomelia phenotype that faithfully replicates the constellation of external and internal malformations, typical of the human condition. These mutants represent an invaluable model in which we have analyzed the pathogenesis of sirenomelia. We show that the signaling defect predominantly impacts the morphogenesis of the hindgut and the development of the caudal end of the dorsal aortas. The deficient formation of ventral midline structures, including the interlimb mesoderm caudal to the umbilicus, leads to the approximation and merging of the hindlimb fields. Our study provides new insights for the understanding of the mechanisms resulting in caudal body malformations, including sirenomelia.     

Genetic and family study of the Apert syndrome

Of 119 patients with the Apert syndrome, 94 pedigrees are available for study. Selected family histories and recorded events during pregnancy are also reported. The sex ratio is 1:1 (60 males, 59 females). All 94 pedigrees except one (an affected father and daughter) represent sporadic instances. Combining our cases with those available in the literature, only nine familial instances are known to date. The familial cases, the equal number of affected males and females, and the increased paternal age in sporadic cases strongly suggest autosomal dominant inheritance. The rarity of familial instances can be explained by reduced genetic fitness of affected individuals because severe malformations and the presence of mental deficiency, found in many cases, diminish desirability as mates. The variability of the syndrome has been defined mainly on the basis of sporadic cases. High resolution banding was normal in five recently studied cases.     

Genetic susceptibility to malignant mesothelioma and exposure to asbestos: the influence of the familial factor

BACKGROUND: Asbestos is the principal etiological factor of malignant mesothelioma (MM), accounting for more than 80% of all tumor cases. However, other co-factors, including genetic susceptibility may play a role in the etiology of this disease, possibly modulating the effects of exposure to asbestos and other carcinogenic mineral fibers. The frequent report of familial clustering was the first indication supporting the involvement of genetic factors. Therefore, we performed an extensive literature search to evaluate existing studies reporting familial cases of MM. METHODS: Published reports addressing the issue of familial susceptibility to MM have been searched through PubMed using keywords and free text tools. Eighty-two citations were retrieved and 20 of them actually reported a familial cluster of MM. Three more articles were identified through the references. The probability that the observed familial clusters of mesothelioma could have randomly occurred in exposed families was evaluated with the Family History Score Zi (FHSi). RESULTS: The result of this analysis suggested that clustering of MM cases in families exposed to asbestos may be explained with the additional contribution of other familial factors. The FHSi allowed to reject the hypothesis of random occurrence of these clusters with a probability of a first type error ranging between 1 per cent and 1 per billion. CONCLUSIONS: The evaluation of the published materials supports the hypothesis that - although familial clustering of MM is largely attributable to shared asbestos exposure - the additional contribution of factors dealing with genetic susceptibility may play a role in the etiology of MM.     

Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome

Hemifacial microsomia (HFM) is a common birth defect involving first and second branchial arch derivatives. The phenotype is extremely variable. In addition to craniofacial anomalies there may be cardiac, vertebral and central nervous system defects. The majority of cases are sporadic, but there is substantial evidence for genetic involvement in this condition, including rare familial cases that exhibit autosomal dominant inheritance. As an approach towards identifying molecular pathways involved in ear and facial development, we have ascertained both familial and sporadic cases of HFM. A genome wide search for linkage in two families with features of HFM was performed to identify the disease loci. In one family data were highly suggestive of linkage to a region of approximately 10.7 cM on chromosome 14q32, with a maximum multipoint lod score of 3.00 between microsatellite markers D14S987 and D14S65. This locus harbours the Goosecoid gene, an excellent candidate for HFM based on mouse expression and phenotype data. Coding region mutations were sought in the familial cases and in 120 sporadic cases, and gross rearrangements of the gene were excluded by Southern blotting. Evidence for genetic heterogeneity is provided by the second family, in which linkage was excluded from this region.     

Heritability and genetic correlation of abdominal and caudal vertebral numbers in latitudinal populations of the medaka <Emphasis Type="Italic">Oryzias latipes</Emphasis>

Body axes of fishes consist of two anatomically distinct types of vertebrae: abdominal and caudal. In the medaka Oryzias latipes, the number of abdominal vertebrae increases with increasing latitudes, whereas caudal vertebrae do not vary systematically across latitudes, suggesting local adaptation in abdominal vertebral numbers. However, because heritable variation in abdominal and caudal vertebral numbers has not been examined within each latitudinal population, it is not clear whether abdominal and caudal vertebrae can evolve independently. Offspring-midparent regression demonstrated substantial heritability of abdominal vertebral numbers in each of two latitudinal populations whereas the heritability of caudal vertebral numbers was not significant. Full-sib analyses revealed that intra-family variation was larger in caudal vertebrae than in abdominal vertebrae, indicating larger non-additive genetic variation and/or larger errors of development in the former. Moreover, the genetic correlation between abdominal and caudal vertebral numbers was very weak. These results suggest that abdominal and caudal vertebrae are controlled by separate developmental modules, which supports their independent evolution with local adaptation of abdominal vertebral numbers in this fish. On the other hand, the weak heritability of caudal vertebrae suggests that the evolution of caudal vertebrae may be restricted, causing unequal evolutionary lability between abdominal and caudal regions.     

Clinico-genetic analysis of omphalocele

The study of 302 cases of omphalocele in foetus and newborns revealed genetic heterogeneity of this congenital malformation. Multiple birth defects were found in 54.3% of probands, including 11% of cases (Wiedemann-Beckwith syndrome being neglected), diagnosed as syndromes with hereditary etiology. The spectrum of anomalies associated with omphalocele in non-classified complexes corresponds to that for caudal regression and cloaca extrophy syndromes. A positive syntropy index for these anomalies shows that these combinations are not coincidental. The increase of omphalocele incidence among relatives of probands with descending gradient, depending on relationship, is demonstrated, which testifies to multifactorial determination of some omphalocele cases. Empirical risk for sibs was 0.6 +/- 0.3% and the index of inheritance was 50.7 +/- 11.4%.     

Role of environment and behaviour in familial resemblances of Plasmodium falciparum infection in a population of Senegalese children

Despite the importance of both environment and behaviour in vector-borne disease epidemiology, these factors are unable to explain alone the distribution of cases in a community and the diversity of clinical presentations, suggesting the involvement of more individual factors such as age, sex, immunity or genetic background. The existence of a genetic factor involved in the susceptibility/resistance to a disease can be suspected by the demonstration of a familial aggregation of cases or by the stability over time of infectious status (infected vs. uninfected; mean level of parasite density (PD), etc.). These familial resemblances can be explained by shared environment, family habits and behaviours (use of bed nets, field activities, etc.). In this preliminary study, we essentially investigated the influence of environment and behaviour on Plasmodium falciparum infection levels and reported the effects of these factors on the existence of familial resemblances. Our results are consistent with the existence of familial resemblances for both the level of P. falciparum infection and the qualitative infection status (QIS) (infected vs. uninfected) that seem to be more related to shared behaviour and environment than to a genetic factor. However, although familial resemblances decreased significantly when adjusted for shared behaviour and environment, this decrease is around 12% for the variability between families, against only 4.5% of that within families. Furthermore, we also demonstrated that the QIS is remarkably stable over time. Both these results are consistent with the hypothesis of the existence of a strong and complex individual factor involved in the control of infection status.     

Influence of landscape and social interactions on transmission of disease in a social cervid

The mechanisms of pathogen transmission are often social behaviours. These occur at local scales and are affected by landscape-scale population structure. Host populations frequently exist in patchy and isolated environments that create a continuum of genetic and social familiarity. Such variability has an important multispatial effect on pathogen spread. We assessed elk dispersal (i.e. likelihood of interdeme pathogen transmission) through spatially explicit genetic analyses. At a landscape scale, the elk population was composed of one cluster within a southeast-to-northwest cline spanning three spatially discrete subpopulations of elk across two protected areas in Manitoba (Canada). Genetic data are consistent with spatial variability in apparent prevalence of bovine tuberculosis (TB) in elk. Given the existing population structure, between-subpopulation spread of disease because of elk dispersal is unlikely. Furthermore, to better understand the risk of spread and distribution of the TB, we used a combination of close-contact logging biotelemetry and genetic data, which highlights how social intercourse may affect pathogen transmission. Our results indicate that close-contact interaction rate and duration did not covary with genetic relatedness. Thus, direct elk-to-elk transmission of disease is unlikely to be constrained to related individuals. That social intercourse in elk is not limited to familial groups provides some evidence pathogen transmission may be density-dependent. We show that the combination of landscape-scale genetics, relatedness and local-scale social behaviours is a promising approach to understand and predict landscape-level pathogen transmission within our system and within all social ungulate systems affected by transmissible diseases.     

Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process

Parkinson disease (PD) is known as a common progressive neurodegenerative disease which is clinically diagnosed by the manifestation of numerous motor and nonmotor symptoms. PD is a genetically heterogeneous disorder with both familial and sporadic forms. To date, researches in the field of Parkinsonism have identified 23 genes or loci linked to rare monogenic familial forms of PD with Mendelian inheritance. Biochemical studies revealed that the products of these genes usually play key roles in the proper protein and mitochondrial quality control processes, as well as synaptic transmission and vesicular recycling pathways within neurons. Despite this, large number of patients affected with PD typically tends to show sporadic forms of disease with lack of a clear family history. Recent genome-wide association studies (GWAS) meta-analyses on the large sporadic PD case–control samples from European populations have identified over 12 genetic risk factors. However, the genetic etiology that underlies pathogenesis of PD is also discussed, since it remains unidentified in 40% of all PD-affected cases. Nowadays, with the emergence of new genetic techniques, international PD genomics consortiums and public online resources such as PDGene, there are many hopes that future large-scale genetics projects provide further insights into the genetic etiology of PD and improve diagnostic accuracy and therapeutic clinical trial designs.