[Spanish rare disease registries research network: first results of Spain-RDR's project in Navarre]. / Red española de registros de enfermedades raras para la investigación: primeros resultados del proyecto Spain-RDR en Navarra.

BACKGROUND: The Spanish Rare Disease Registries Research Network, Spain-RDR, was a project of the Carlos III Health Institute (2012-2015) in which all the Autonomous Communities participated. The initial results for Navarre are presented. METHODS: The Minimum Basic Data Set for 2010-2011 was explored to assess the collection of possible cases of rare diseases in Navarre (pilot study). The information was later extended in both time (the year 2012) and sources consulted (Mortality Statistics and Temporary Disability Registry). RESULTS: Navarre identified 9,420 possible cases amongst the 8,141 residents in the pilot study, reaching 13,494 cases amongst the 11,644 people obtained with the extension of time and sources. Thirty-eight percent of the cases corresponded to endocrine, metabolic and immune diseases, and congenital anomalies. CONCLUSIONS: It is necessary to expand the sources and the period of data collection, as well as to validate the cases registered in order to know the real magnitude of the problem as a whole and for each specific disease included in the registry.

[Demographic characteristics of Down's syndrome in Navarra. Trends of pre and postnatal diagnosis for the period 1991-2009]. / Caracteristicas demograficas del sindrome de Down en Navarra. evolucion del diagnostico pre y postnatal durante el periodo 1991-2009.

This study describes the development of pre and postnatal diagnosis of sindrome de Down (SD) in the Autonomous Community of Navarre from 1991 to 2009 and assesses its preventive impact in the population, as well as to associated socio-demographic changes. In the absence of a prenatal diagnosis for DS, the change in maternal age from 1991 to 2009 would have caused a 50% increase in births with this disorder. However, the antenatal rate detection of DS increased from 15.8% in 1991-4 to 64.3% in 2006-9, giving rise to a decreasing incidence trend, not statistically significant, during the study period and to a higher mean age of mothers of live births with DS (32.75± 5,02 and 34.8±4,82 years during the first and second periods of the study, respectively). The proportion of young mothers (<35 years) of live births with DS was 66% in 1991-4 and 45% in 2006-9. Close to one fifth of the total population of pregnant women, however, did not want to go through a maternal screening test or amniocentesis. Seventeen per cent of all live births with DS had a positive screening test, but mothers decided to continue pregnancy. These results suggest that, despite the application of new and more sensitive prenatal screening tests, the incidence of DS may still be relatively high in our population, an important factor to be considered for future antenatal preventive programs and adequate postnatal care.

Repeat instability in the 27-39 CAG range of the HD gene in the Venezuelan kindreds: Counseling implications.

The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from 11 to 82 years. We expect these findings to be helpful in updating genetic counseling practices.

Modifying effect of HLA haplotypes located trans to DQB1*02-DRB1*03 in celiac patients of Southern Europe.

The DQ2 heterodimer, encoded by the human leukocyte antigen (HLA)-DQA1*05-DQB1*02 alleles, is the major genetic susceptibility factor for celiac disease (CD). However, the risk associated to HLA alleles varies among populations. While DRB1*03 is almost the only CD susceptibility allele in Northern Europe with a homozygote frequency of around 30%, CD in south European countries is also associated with the DRB1*07, and DRB1*03 homozygotes patients are rare. Some authors have suggested that DQB1*02-DRB1*03/DQB1*02-DRB1*03 and DQB1*02-DRB1*03/DQB1*02-DRB1*07 may confer different risk susceptibility to CD. This hypothesis, however, has not been demonstrated in a recent family-based study carried out in Finland, suggesting that the proposed differences in risk may be secondary to stratification burdens of case-control studies. To assess this issue, we have investigated the effect of different haplotypes carried trans to DQB1*02-DRB1*03 as additional factors for CD in Spain, using two statistical approaches, a case-control study and a family-based study. We found that DQB1*02-DRB1*03/DQB1*02-DRB1*03 and DQB1*02-DRB1*03/DQB1*02-DRB1*07 were the only combinations that showed a strong and independent association to CD. We did not observe any difference in susceptibility risk conferred by DQB1*02-DRB1*03 and DQB1*02-DRB1*07 when carried trans to DQB1*02-DRB1*03, suggesting that variation in HLA haplotype frequencies among populations may not represent real differences in risk to CD development. We also confirmed a gene dosage effect of the DQB1*02-DRB1*03 haplotype estimating that DQB1*02 homozygotes are at fivefold increased risk for CD compared with DQB1*02 heterozygotes. This risk is conferred by the second copy of the DQB1*02 allele and it seems to be independent of the DQA1.

Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families.

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease, characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries. Recently, SLC2A10 mutations were identified in this condition. This gene encodes the glucose transporter GLUT10 and was previously suggested as a candidate gene for diabetes mellitus type 2. A total of 12 newly identified ATS families with 16 affected individuals were clinically and molecularly characterized. In addition, extensive cardiovascular imaging and glucose tolerance tests were performed in both patients and heterozygous carriers. All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel (six missense, three truncating mutations, including a large deletion). Haplotype analysis suggests founder effects for all five recurrent mutations. Remarkably, patients were significantly older than those previously reported in the literature (P=0.04). Only one affected relative died, most likely of an unrelated cause. Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years. Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, seven patients had localized arterial stenoses, and five had long stenotic stretches of the aorta. Heterozygous carriers did not show any vascular anomalies. Glucose metabolism was normal in six patients and eight heterozygous individuals of five families. As such, overt diabetes is not related to SLC2A10 mutations associated with ATS.

[Genetic mechanisms in the hereditary predisposition to colorectal cancer]. / Mecanismos genéticos en la predisposición hereditaria al cáncer colorrectal.

A proportion of colorectal cancers shows some type of genetic predisposition that can be recognised in clinical practice. From the classical dominant inheritance pattern of familial adenomatous polyposis or hereditary non-polyposis colorectal cancer, through the recessive transmission of the MYH associated polyposis, to the new syndromes of the "serrated pathway" or low-penetrance alleles, the discovery of new genes and a deeper understanding of the mechanisms of action of already-known ones are enabling us to understand new aspects of the colorectal carcinogenesis. This is throwing a new light on some of the observed familial aggregation patterns which had remained unexplained.

Incidence and mutation rates of Huntington's disease in Spain: experience of 9 years of direct genetic testing.

BACKGROUND: Prior to the discovery of the Huntington's disease (HD) mutation, the prevalence, incidence, and new mutation rates for this disease were based on the presence of progressive choreic movements and a positive family history. OBJECTIVE: To evaluate the uptake of the HD genetic analysis in Spain, and to provide additional information on the epidemiology of this disease from the experience of 9 years of direct genetic testing. METHODS: From 1994 to 2002, CAG repeat length was determined in 317 patients with symptoms compatible with HD. In all cases, demographic, clinical, and family data were carefully reviewed. RESULTS: HD diagnosis (CAG repeat length >/=36) was confirmed in 166 (52%) symptomatic cases. Of these, 76 (45.8%) reported a positive family history and in 21 cases (12.7%) family history was negative. New mutation events were genetically proven in three families and highly suspected in another, estimating that the minimum new mutation rate for HD in our population is >4%, with a potential mutation rate of 8%. More than 16% of all HD cases had late onset (>59 years) of symptoms, and in three quarters of these the family history was negative. The incidence rate for the autonomous communities of Navarra and the Basque country, based on the number of newly diagnosed cases by genetic testing, was 4.7 per million per year. CONCLUSIONS: Direct HD genetic testing shows that the incidence and mutation rates of the disease are 2-3 times higher than previously reported. We also demonstrated the relevance of CAG repeat length assessment in diagnosing patients with late onset of symptoms and negative family history for HD.

Heat-shock protein 70-1 and HLA class II gene polymorphisms associated with celiac disease susceptibility in Navarra (Spain).

Heat shock proteins (HSP) are thought to play a role in the immune response making probable their contribution to celiac disease (CD). We studied the polymorphisms in the 5' regulatory region of the HSP70-1 gene and performed genomic HLA-DQ and -DR typing in 128 CD patients and 94 healthy controls from Navarra (Spain). The frequency of the C allele of the HSP70-1, characterized by the intermediate electrophoretic mobility of DNA, was significantly increased among CD patients (64.5% vs 37.2%. p <1 x 10(-7)). When subjects were stratified by the HLA II genotype, differences were statistically significant between DR3-negative or DR3-DQB1*02-negative CD patients and matched controls. Homozygosity for the DQB1*02 allele was present in 48.4% of CD patients and 12.8% of controls (OR = 6.4; CI:3.1 to 13.8; p <1 x 10(-7)). Similar increased risk was observed for DQB1*02/*02, DRB1*03/-, or DRB1*03/07 patients. Furthermore, those individuals expressing the classical HLA alleles in CD (DQB1*02/*02, DRB1*03/*07) who also carried the HSP70-1 CC genotype were twelve times more likely to develop the disease than the matched controls. We therefore conclude that although HSP70-1 gene does not seem to be primarily associated with CD, it might be a component of the high risk haplotype, playing a role as an additional predisposing gene for the disease.

Familial choanal atresia with maxillary hypoplasia, prognathism, and hypodontia.

We report on two sibs and a cousin with bilateral choanal atresia. At 2 months, one sib died of complications following surgical correction of her defects. We evaluated her brother and cousin at age 7 and 9 years, respectively. Both had a tall forehead, maxillary hypoplasia, prognathism, and absence of certain deciduous and permanent teeth. Psychomotor development was appropriate for age. Roentgenocephalometric analyses of several relatives showed that one grandfather of these children and two of the five uncles and aunts also had maxillary hypoplasia and/or prognathism. To our knowledge, this condition has not been described previously and may represent a newly recognized autosomal dominant condition with incomplete penetrance and variable expressivity caused by a defect of neural crest development.

A new autosomal recessive retinitis pigmentosa locus maps on chromosome 2q31-q33.

Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disease. To date, mutations in four members of the phototransduction cascade have been implicated in ARRP. Additionally, linkage of the disease to three loci on 1p, 1q, and 6p has been described. However, the majority of cases are still uncharacterised. We have performed linkage analysis in a large nuclear ARRP family with five affected sibs. After exclusion of several regions of the genome known to contain loci for retinal dystrophies, a genomic search for linkage to ARRP was undertaken. Positive lod scores were obtained with markers on 2q31-q33 (Zmax at theta = 0.00 of 4.03, 4.12, and 4.12 at D2S364, D2S118, and D2S389, respectively) defining an interval of about 7 cM for this new ARRP locus, between D2S148 and D2S161. Forty-four out of 47 additional ARRP families, tested with markers on 2q32, failed to show linkage, providing evidence of further genetic heterogeneity.

Down syndrome: characterisation of a case with partial trisomy of chromosome 21 owing to a paternal balanced translocation (15;21) (q26;q22.1) by FISH.

A patient with a typical Down syndrome (DS) phenotype and a normal karyotype was studied by FISH. Using painting probes, we found that the patient had partial trisomy of chromosome 21 owing to an unbalanced translocation t(15;21) (q26; q22.1) of paternal origin. To correlate genotype with phenotype as accurately as possible, we localised the breakpoint using a contig of YACs from the long arm of chromosome 21 as probes and performed FISH. We ended up with two YACs, the most telomeric giving signal on the der (15) in addition to signal on the normal chromosome 21 and the most centromeric giving signal only on both normal chromosomes 21. From these results we could conclude that the breakpoint must be located within the region encompassing YACs 280B1 and 814C1, most likely near one end of either YAC or between them, since neither YAC814C1 nor 280B1 crossed the breakpoint (most likely between marker D21S304 and marker D21S302) onband 21q22.1. The same study was performed on the chromosomes of the father and of a sister and a brother of the patient; all three carried a balanced translocation between chromosomes 15 and 21 and had a normal phenotype. We also performed a prenatal study using FISH for the sister. The fetus was also a carrier of the balanced translocation.

Homozygous tandem duplication within the gene encoding the beta-subunit of rod phosphodiesterase as a cause for autosomal recessive retinitis pigmentosa.

Autosomal recessive retinitis pigmentosa (ARRP) is a degenerative disease of photoreceptors in which defects in the rhodopsin and phosphodiesterase beta-subunit (PDEB) loci have been reported. To assess the involvement of PDEB in ARRP families from Spain, we screened a panel of 19 families for linkage to markers within or close to the PDEB gene. Homozygosity was also tested in cases of consanguinity. This combined approach ruled out PDEB as the cause of the disease in all but one of the families. Molecular characterization of the gene in that family (a consanguineous pedigree) revealed a homozygous 71-bp tandem duplication in exon 1 of the affected member, the parents being heterozygous. This defect causes a frameshift mutation which leads to a premature stop codon, suggesting that this mutant allele is the underlying cause of ARRP in this patient. According to the data presented here, the PDEB gene is not the main gene responsible for ARRP, but accounts for about 5% of the cases.

Further delineation of pseudotrisomy 13 syndrome: a case without polydactyly.

We report on a baby with holoprosencephaly, median cleft lip, cardiac and genital anomalies, normal upper limbs, and a 46,XX karyotype. We also reviewed 22 karyotypically normal cases whose clinical features resembled trisomy 13 syndrome and compared them with the case we present. The problem of variable expression of the pseudotrisomy 13 syndrome versus genetic heterogeneity is illustrated.

Maternal diabetes: the risk for specific birth defects.

We studied the risk for specific birth defects among infants of mothers with gestational and chronic diabetes using data collected by the Spanish Collaborative Study of Congenital Malformations (ECEMC). For the years 1976 to 1985, we identified 10,087 infants with malformations and 9,994 control infants; 155 of the case infants and 89 of the controls were born to diabetic mothers. The crude odds ratio for any minor or major defect and insulin-treated diabetes was 5.5 (95% CI = 1.2, 24.8), and for major malformations it was 8.7 (95% CI = 1.8, 34.7). The risk for defects involving the central nervous system (CNS), skeletal system and cardiovascular system were significantly increased. Infants of non-insulin-treated diabetic mothers were 2.9 times more likely to have a major congenital birth defect (95% CI = 1.2, 7.2). The crude odds ratio for any major or minor defect and mothers with gestational diabetes requiring insulin was 1.9 (95% CI = 1.1, 3.4). Similar risk was observed for major defects (OR = 1.9, 95% CI = 1.0, 3.7). These results suggest that infants of insulin-treated diabetic mothers have an increased risk of developing malformations of the CNS, cardiovascular system and skeletal system. We also found an increased risk for specific defect categories among infants of mothers with gestational diabetes treated with insulin.

Weaver syndrome: a case without early overgrowth and review of the literature.

A female child with Weaver syndrome is described. She did not show the excessive growth characteristic of this syndrome until after adequate caloric intake was achieved by feeding through a gastric feeding tube. Her inadequate nutrition was a result of feeding difficulties during infancy. In addition, she had recurrent pulmonary infections, apneic spells, and severe developmental delay. She died at 16 months of sepsis, congestive heart failure, and respiratory arrest. The autopsy revealed marked atrophy of the brain and cardiac ventricular hypertrophy. Most of the brain changes were thought to be from hypoxia.