Expanding the Etiology of Oculo-Auriculo-Vertebral Spectrum: A Novel Interstitial Microdeletion at 1p36.

The etiology of oculo-auriculo-vertebral spectrum (OAVS) is not well established. About half of patients show a positive family history. The etiology of familiar cases is unclear but appears genetically heterogeneous. This motivated us to report a case of OAVS with microtia, ptosis, facial microsomy, and fusion of vertebral bodies associated with a novel genetic etiology, including a deletion at 1p36.12-13. This case report expands on the genetic etiology of OAVS. Furthermore, it also expands the clinical manifestations of patients with interstitial deletions of the de 1p36.12-13 region.

A unique case of a discontinuous duplication 3q26.1-3q28 resulting from a segregation error of a maternal complex chromosomal rearrangement involving an insertion and an inversion.

Until now, few cases of partial trisomy of 3q due to segregation error of parental balanced translocation and segregation of a duplicated deficient product resulting from parental pericentric inversion have been reported so far. Only five cases of chromosomal insertion malsegregation involving 3q region are available yet, thus making it relatively rare. In this case report, we are presenting a unique case of discontinuous partial trisomy of 3q26.1-q28 region which resulted from a segregation error of two insertions involving 3q26.1 to 3q27.3 and 3q28 regions with ~21Mb and ~2Mb sizes, respectively. The maternally inherited insertion was cytogenetically characterized as der(8)(8pter→8p22::3q26→3q27.3::3q28→3q28::8p22→8qter) and the patient's major clinical features involved Dandy Walker malformation, sub-aortic ventricular septal defect, upslanting palpebral fissures, clinodactyly, hirsutism, and prominent forehead. Besides, a review of the literature involving cases with similar chromosomal imbalances and cases with "3q-duplication syndrome" is also provided.

The spectrum of SCN5A gene mutations in Spanish Brugada syndrome patients.

Brugada syndrome is characterized by right bundle branch block and ST-segment elevation in the right precordial ECG leads. Familial transmission is frequent and approximately 25% of cases exhibit mutations in the SCN5A gene. We analyzed the sequence of this gene in 25 Spanish patients with Brugada syndrome. In 4 (16%), we found mutations that had not previously been described: three were amino acid changes (i.e. Ala2>Thr, Ala735>Thr and Val1340>Ile) and one was an intron mutation that affected messenger RNA processing (i.e. IVS18-1G>A). These four patients had relatives who were also mutation carriers, several of whom had normal ECGs, even on flecainide challenge. Our study suggests that genetic analysis could be helpful in the presymptomatic diagnosis of Brugada syndrome, but may be less useful for stratifying the risk of adverse events.

Espectro mutacional del gen SCN5A en pacientes españoles con síndrome de Brugada / The spectrum of SCN5A gene mutations in spanish Brugada syndrome patients

El síndrome de Brugada se caracteriza por un bloqueo de la rama derecha y elevación del segmento ST en las derivaciones precordiales derechas del electrocardiograma. Con frecuencia se observa una transmisión familiar, y en aproximadamente el 25% de los casos se han hallado mutaciones en el gen SCN5A. Hemos analizado la secuencia de este gen en 25 pacientes españoles con síndrome de Brugada. En 4 de ellos (16%) hallamos mutaciones que no habían sido descritas previamente: 3 eran cambios de aminoácidos (Ala2>Tre, Ala735>Tre y Val1340>Ile) y 1 era intrónica y afectaría al procesamiento del ARNm (intrón 18 IVS18-1G>A). En los 4 había familiares portadores, y varios de ellos tenían electrocardiogramas normales, incluso tras inducción con flecainida. Nuestro estudio indica que el análisis genético sería útil para el diagnóstico presintomático, pero de utilidad limitada para estratificar el riesgo de eventos adversos (AU)

Brugada syndrome is characterized by right bundle branch block and ST-segment elevation in the right precordial ECG leads. Familial transmission is frequent and approximately 25% of cases exhibit mutations in the SCN5A gene. We analyzed the sequence of this gene in 25 Spanish patients with Brugada syndrome. In 4 (16%), we found mutations that had not previously been described: three were amino acid changes (i.e. Ala2>Thr, Ala735>Thr and Val1340>Ile) and one was an intron mutation that affected messenger RNA processing (i.e. IVS18-1G>A). These four patients had relatives who were also mutation carriers, several of whom had normal ECGs, even on flecainide challenge. Our study suggests that genetic analysis could be helpful in the presymptomatic diagnosis of Brugada syndrome, but may be less useful for stratifying the risk of adverse events (AU)

Cuándo practicar un análisis genético molecular en pacientes con miocardiopatía hipertrófica: [revisión] / Hypertrophic cardiomyopathy: who should be screened and when?: [review]

La miocardiopatía hipertrófica (MCH) es una enfermedad frecuentemente hereditaria, causada por mutaciones en varios genes implicados en el funcionamiento del sarcómero cardíaco. Aunque hay más de 12 genes en los que se han hallado mutaciones, la mayoría de los pacientes o sus familias tienen una mutación en el gen MYH7, MYBPC3, TNNT2, TNNI3, o TPM1. Dado que los parámetros clínico-patológicos tienen una capacidad limitada para predecir los efectos adversos, se ha investigado la posibilidad de emplear los hallazgos genéticos con este fin (por ejemplo, para predecir el riesgo de muerte súbita) y en la toma de decisiones terapéuticas. Actualmente, podemos concluir que para la mayoría de las mutaciones no se puede derivar un comportamiento clínico definido, algo que se podía suponer si consideramos que las manifestaciones de la MCH son heterogéneas, incluso entre los afectados de una misma familia. En este artículo revisamos los aspectos fundamentales de los análisis moleculares con fines diagnósticos en la MCH y las posibilidades de aplicar los hallazgos genéticos en la toma de decisiones.

Cuándo practicar un análisis genético molecular en pacientes con miocardiopatía hipertrófica: [revisión] / Hypertrophic cardiomyopathy: who should be screened and when?: [review]

La miocardiopatía hipertrófica (MCH) es una enfermedad frecuentemente hereditaria, causada por mutaciones en varios genes implicados en el funcionamiento del sarcómero cardíaco. Aunque hay más de 12 genes en los que se han hallado mutaciones, la mayoría de los pacientes o sus familias tienen una mutación en el gen MYH7, MYBPC3, TNNT2, TNNI3, o TPM1. Dado que los parámetros clínico-patológicos tienen una capacidad limitada para predecir los efectos adversos, se ha investigado la posibilidad de emplear los hallazgos genéticos con este fin (por ejemplo, para predecir el riesgo de muerte súbita) y en la toma de decisiones terapéuticas. Actualmente, podemos concluir que para la mayoría de las mutaciones no se puede derivar un comportamiento clínico definido, algo que se podía suponer si consideramos que las manifestaciones de la MCH son heterogéneas, incluso entre los afectados de una misma familia. En este artículo revisamos los aspectos fundamentales de los análisis moleculares con fines diagnósticos en la MCH y las posibilidades de aplicar los hallazgos genéticos en la toma de decisiones.(AU)

Lack of association between endothelin-1 gene variants and myocardial infarction.

AIM: Endothelin-1 (ET-1) promotes vasoconstriction and cell proliferation, and has been implicated in hypertension and coronary artery disease. Our aim was to analyse the role of the ET-1 gene (EDN1) in the risk for atherosclerosis/myocardial infarction (MI) in a population with smoking as the prevalent risk factor. METHODS: The study included 316 patients with early onset MI (<55 years old). All were male with at least one diseased coronary vessel. Denaturing high performance liquid chromatography (DHPLC), single-strand conformation analysis (SSCA), and direct sequencing were used to search for DNA variants in the five EDN1 exons and the promoter region. To determine the association of EDN1 polymorphisms with MI, we genotyped the patients and controls (n=350) and compared the allele and genotype frequencies between groups. RESULTS: We found six common nucleotide changes: -1394 (T/G) and -974 C/A (promoter), +120 ins/del A (exon 1, 5' UTR), 568 A/G (exon 3, E106E), 844 G/T (exon 5, K198N), and 1617 T/C (exon 5, 3' UTR). No rare EDN1-variants specific to the MIpatients were found. None of the EDN1 polymorphisms were significantly associated with early-onset MI in our population. The two promoter polymorphisms were in linkage disequilibrium with K198N, but no haplotype was associated with MI risk. CONCLUSIONS: In our population, the EDN1 variation did not contribute to early-onset MI.

Clinical and analytical findings in Gitelman's syndrome associated with homozygosity for the c.1925 G>A SLC12A3 mutation.

BACKGROUND: Gitelman's syndrome (GS) is caused by mutations in the SLC12A3. Most of the mutations are rare, making it difficult to establish a genotype-phenotype correlation. Although GS is a recessive disorder, some patients also have an affected parent, suggesting a dominant inheritance. METHODS: We sequenced the 26 coding exons of SLC12A3 in a family in which the proband and her father had a late onset GS. We obtained cDNA of the 2 patients and analyzed the effect of a mutation on pre-mRNA splicing. RESULTS: The 2 patients were homozygous for a nucleotide change in the last nucleotide of exon 15: c.1925 G>A. The mother was a heterozygous carrier for this putative mutation. Amplification of cDNA with primers for exons 14-17 was negative, suggesting that this mutation affected the splicing and promoted mRNA degradation through nonsense-mediated decay. CONCLUSIONS: We report a family with 2 patients with late onset GS and homozygous for a mutation in the last nucleotide of exon 15. Our study shows that homozygosity for this mutation resulted in a significant loss of normal SLC12A3 transcript.

[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. / Espectro mutacional de los genes sarcoméricos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en pacientes con miocardiopatía hipertrófica.

INTRODUCTION AND OBJECTIVES: Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy. METHODS: We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated. RESULTS: In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1 and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had two mutations (i.e., double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations. CONCLUSIONS: Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.

Espectro mutacional de los genes sarcoméricos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en pacientes con miocardiopatía hipertrófica / Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy

Introducción y objetivos. Desarrollar un análisis coste-efectividad de un programa de cribado genético de familares de primer grado de pacientes con hipercolesterolemia familiar (HF), seguido de tratamiento cuando fuera necesario, frente a la alternativa de no cribar. Métodos. Se realiza un análisis coste-efectividad en el cual se modeló el efecto del tratamiento con estatinas en personas diagnosticadas de HF tras el cribado genético. La incertidumbre se trató mediante análisis de sensibilidad univariable y probabilístico. La estrategia alternativa considerada es no cribar. El análisis coste-efectividad considera como resultado sobre la salud los años de vida ganados (AVG) e incluye los costes del cribado, tratamiento con estatinas, visitas al especialista y hospitalizaciones. Asimismo, se calculó el valor esperado de la información perfecta, como complemento del análisis de sensibilidad. Resultados. En el caso base, el coste incremental por AVG del programa de cribado a pacientes directos asciende a 3.423 euros/AVG. Los resultados varían en el análisis de sensibilidad, pero las conclusiones son robustas frente a cambios en los parámetros considerados. El programa de cribado es óptimo frente a la alternativa considerada, con un 95% de probabilidad si la disposición a pagar, social o del decisor sanitario, fuera de al menos 7.400 euros/AVG. Conclusiones. El análisis señala que el programa de cribado genético más tratamiento en familiares directos de personas con HF presenta una buena relación incremental de coste-efectividad frente a la alternativa de no cribar (AU)

Introduction and objectives. The aim was to assess the cost-effectiveness of a genetic screening program for first-degree relatives of patients with familial hypercholesterolemia (FH), followed by treatment when necessary, compared with the alternative of no screening. Methods. The cost-effectiveness analysis modeled the effect of statin treatment on individuals who were diagnosed with FH after genetic screening. The impact of uncertainty was evaluated using univariate probabilistic sensitivity analysis. The alternate strategy considered was no screening. In the cost-effectiveness analysis, the number of life-years gained (LYG) was regarded as the health outcome and the costs of screening, statin treatment, specialist consultations and hospital visits were all included. In addition, the expected value of perfect information was calculated as part of the sensitivity analysis. Results. In the base case, the incremental cost of the screening program for close relatives was 3423 euros per LYG. Although the sensitivity analysis gave a range of results, the conclusions were not affected by changes in the parameters considered. The screening program was found to be better than the alternative considered at a probability level of 95% if the acceptable level of health-care costs was at least 7400 euros per LYG. Conclusions. This analysis indicates that a genetic screening program, supplemented by treatment, for the close relatives of individuals with FH is preferable to the alternative of no screening in terms of incremental cost-effectiveness (AU)

A search for cyclophilin-A gene variants in cyclosporine A-treated renal transplanted patients.

BACKGROUND: The cyclophilin A (CypA)-cyclosporine (CsA) complex promotes immune response. The variation at the CypA gene could explain CsA-pharmacokinetics and clinical outcomes among CsA-treated patients. METHODS: The study included 290 kidney transplanted patients (65% male; mean age 51 +/- 15 yr), treated with CsA. The five CypA- exons and the promoter region were analysed through single-strand conformation analysis, denaturing high performance liquid chromatography, and direct sequencing. The effect of a promoter polymorphism (-11 G/C) on gene expression was analysed in cell-cultures. RESULTS: We found two polymorphisms in the promoter (-11 G/C) and exon 1 (+36 G/A). Genotype frequencies did not differ between patients according to their pharmacokinetics status. In vitro studies showed that -11 G/C affected gene expression. The -11 G allele was significantly associated with clinical nephrotoxicity (p = 0.006). The strongest predictors for nephrotoxicity were a donor age > or =55 yr, and the promoter GG + GC genotypes. CONCLUSIONS: Our work suggests that a CypA-promoter polymorphism (-11 G/C) could be associated with clinical nephrotoxicity. Replication of this study in other populations is necessary to define the role of CypA-variants in the main clinical outcomes among CsA-treated kidney-transplanted patients.

Sequence analysis of myozenin 2 in 438 European patients with familial hypertrophic cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is an allelic cardiac disorder characterized by increased ventricular wall mass and sudden cardiac death. A variety of dominant single-gene mutations in sarcomeric genes have been identified, indicating a highly heterogeneous genetic etiology. MYOZ2 encodes for sarcomeric calsarcin-1 located in the myocardial z-disc, a focal point of HCM disease genes. Very recently mutations in MYOZ2 were reported as a cause for HCM. To assess the prevalence of MYOZ2 mutations among European HCM patients, coding exons weree analyzed for genetic variants in 438 patients. MATERIAL/METHODS: Four hundred thirty-eight patients with HCM in four European cardiovascular centers were recruited. The coding region of MYOZ2 was directly sequenced in all the HCM subjects. RESULTS: Two non-synonymous polymorphisms in exon 2 (rs17851524) and exon 5 (rs7687613) of MYOZ2 were identified in eight and twenty-two patients, respectively. However, no disease-causing mutations could be identified in this large cohort of HCM patients. CONCLUSIONS: Although a large cohort of more than 400 patients with familial HCM was screened, a disease-associated mutation in MYOZ2 was not identified. When these results are combined with previous reports, it can be concluded that MYOZ2 mutations are rare causes of familial HCM.

Mitochondrial transcription factor A (TFAM) gene variation and risk of late-onset Alzheimer's disease.

Impaired mitochondrial function and an increased number of mutations in mitochondrial DNA (mtDNA) has been found in brains of patients with late-onset Alzheimer's disease (LOAD). The TFAM-gene encodes the mitochondrial transcription factor A, a protein that controls the transcription, replication, damage sensing, and repair of mtDNA. TFAM is on human chromosome region 10q21.1, where a locus for LOAD has been mapped. Our objective was to determine the role of TFAM-gene variation in the risk of LOAD. The seven TFAM coding exons were analysed through single strand conformation analysis and direct sequencing in a cohort of Spanish LOAD-patients and healthy controls. We found four common polymorphisms, two in the flanquing intronic and two in the coding sequences. Polymorphism rs1937 (+35 G/C) was the only missense change (S12T). Genotyping of this polymorphism in 300 LOAD-patients and 183 healthy controls showed a significantly higher frequency of GG-homozygotes in the patients (92% vs. 86%; p=0.04; OR=1.91, 95%CI=1.02-3.50). This suggests that S12 is a risk factor for LOAD in our population. In conclusion, rare variants (mutations) in the TFAM gene were not found in LOAD-patients, but the S12T polymorphism was a moderate risk factor for LOAD in our population.

[Usefulness of the ECG in the sports screening of footballers affiliated to a regional sports federation]. / Rendimiento del estudio electrocardiográfico en el reconocimiento deportivo de futbolistas federados de una comunidad autónoma.

We report the results of a study carried out in 825 young football club members, all of whom underwent screening for hypertrophic cardiomyopathy using a 12-lead ECG. Echocardiographic assessment was performed in only those with positive ECG results, as defined by the European Society of Cardiology. Echocardiography proved necessary in 61 (7%) individuals with positive ECG findings, of whom 7 had echocardiographic findings indicative of left ventricular hypertrophy: five were in the "gray zone", 1 was judged to have athlete's heart, and one had been diagnosed with hypertrophic cardiomyopathy. In all these cases, ECG showed repolarization abnormalities, and 4 satisfied criteria for left ventricular hypertrophy.

Rendimiento del estudio electrocardiográfico en el reconocimiento deportivo de futbolistas federados de una comunidad autónoma / Usefulness of the ECG in the sports screening of footballers affiliated to a regional sports federation

Presentamos un estudio realizado sobre 825 futbolistas federados de las categorías juvenil y superiores, en el que se procede al cribado de miocardiopatía hipertrófica mediante electrocardiograma (ECG) de doce derivaciones; se practicó ecocardiograma sólo en los casos con ECG definido como positivo siguiendo los criterios de la Sociedad Europea de Cardiología (ESC). Fue preciso realizar estudio ecocardiográfico a 61 (7%) futbolistas con ECG positivo; 7 presentaron criterios ecocardiográficos de hipertrofia ventricular izquierda, 5 estaban en la «zona gris», se consideró a 1 sujeto como corazón de deportista y otro estaba diagnosticado de miocardiopatía hipertrófica. En todos, el ECG mostró alteraciones de la repolarización y en 4, criterios de crecimiento ventricular izquierdo

We report the results of a study carried out in 825 young football club members, all of whom underwent screening for hypertrophic cardiomyopathy using a 12-lead ECG. Echocardiographic assessment was performed in only those with positive ECG results, as defined by the European Society of Cardiology. Echocardiography proved necessary in 61 (7%) individuals with positive ECG findings, of whom 7 had echocardiographic findings indicative of left ventricular hypertrophy: five were in the "gray zone", 1 was judged to have athlete's heart, and one had been diagnosed with hypertrophic cardiomyopathy. In all these cases, ECG showed repolarization abnormalities, and 4 satisfied criteria for left ventricular hypertrophy

Mitochondrial transcription factor A (TFAM) gene variation in Parkinson's disease.

Mitochondrial function is necessary to supply the energy required for cell metabolism. Mutations/polymorphisms in mitochondrial DNA (mtDNA) have been implicated in Parkinson's disease (PD). The mitochondrial transcription factor A (TFAM) controls the transcription of mtDNA and regulates the mtDNA-copy number, thus being important for maintaining ATP production. TFAM dysfunction may also be involved in PD, and TFAM gene mutations/polymorphisms could contribute to the risk of developing PD. We searched for gene variants in the seven TFAM-exons in a total of 250 PD-patients. We found five common polymorphisms, and only one was a missense change (S12T in exon 1). Genotype and allele frequencies did not differ between patients and healthy controls (n=225) for the five polymorphisms. Our work suggests that TFAM-variants did not contribute to the risk of developing PD.

Prevalence and spectrum of mutations in the sarcomeric troponin T and I genes in a cohort of Spanish cardiac hypertrophy patients.

We sequenced the coding exons of the cardiac troponins T (TNNT2) and I (TNNI3) genes in 115 Spanish HCM-patients (32% with a family history of the disease). Only two (2%) had mutations in the TNNT2 (Arg278>Cys and Arg92>Lys). These mutations were associated with variable clinical outcomes. No patient had TNNI3-mutation. We also genotyped these patients and 320 healthy controls for a 5 bp insertion/deletion (I/D) polymorphism in intron 3 of TNNT2. DD-homozygotes for the 5 bp I/D polymorphism were significantly more frequent among the patients (OR=1.83, 95% CI=2.10-5.16).

Myocyte enhancing factor-2A in Alzheimer's disease: genetic analysis and association with MEF2A-polymorphisms.

Polymorphisms at different genes have been proposed as determinants of the risk for developing late-onset Alzheimer's disease (LOAD). Among the several candidate genes are those that encode proteins involved in neuronal degeneration/survival. Studies of primary neuronal cultures supported that members of the myocyte enhancing factor-2 (MEF2) family of transcription factors have an anti-apoptotic effect, regulating the expression of proteins involved in neuronal survival and differentiation. We analysed the MEF2A gene in a total of 357 patients (mean age 72 years, range 60-97 years). Among others, a Pro279Leu in exon 8 and a polyglutamine (CAG) repeat polymorphisms in exon 12 were found. These variants were also genotyped in 495 healthy controls (>50 years old), and the frequencies were statistically compared. Eight patients were 279L (six P/L and two L/L), compared to only one control (2% vs. 0.2%; p=0.004, OR=11.32). There was a significantly higher frequency of 279L-carriers among APOE epsilon4+ (7/154=4.5%), compared to epsilon4- (1/203) (p=0.02). In conclusion, our work suggests that the variation at the MEF2A gene could be involved in the risk of developing LOAD. Because MEF2 has been related with neuronal survival, and the 279L allele has been related with a reduction in the transcriptional activation activity of MEF2A, the effect of this allele could be mediated through a down-regulation of antiapoptotic genes.

ABCA1 polymorphisms and prognosis after myocardial infarction in young patients.

High-density cholesterol (HDL) levels are affected by genetic influences and certain behaviors. Low levels of HDL-C are considered as an independent risk factor for premature coronary heart disease. In patients with Tangier disease, characterised by low HDL levels, mutations in the ATP binding cassette transporter have been described. We have analysed three polymorphisms of the ABCA1 gene (-477C/T, R219 K, and I883M) in a cohort of young male survivors of myocardial infarction in order to know their influence in long-term prognosis. In premature heart disease, knowing prognosis factors is specially relevant.

Hypertrophic cardiomyopathy linked to homozygosity for a new mutation in the myosin-binding protein C gene (A627V) suggests a dosage effect.

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are responsible for up to 50% of familial cases with hypertrophic cardiomyopathy (HC). Compared to patients with mutations in other sarcomeric genes, patients with MYBPC3 mutations would have a milder form of the disease, with a lower incidence of sudden cardiac death. Because most of the mutations have been found in only one family, it is currently difficult to establish a correlation between a particular mutation and the HC phenotype. The aim of our study was to contribute to understanding of the role of MYBPC3 mutations in HC. We analysed the MYBPC3 exons and intron flanking regions in 10 patients from 10 families with at least two HC cases. After direct sequencing of polymerase chain reaction (PCR) fragments, we found three new mutations in three families (V771M, V342D, and A627V). These changes affected evolutionary conserved amino acids and were not found in 100 healthy controls. The Ala 627>Val was found homozygous in a 47-year-old patient with a severe form of HC, while his mother and a nephew were heterozygous carriers and asymptomatic. This fact suggests a dosage effect for mutations at the MYPBC3 gene.