Evidence for genetic heterogeneity in Carvajal syndrome.

International audienceCarvajal syndrome is a rare syndrome with woolly hair, palmoplantar keratosis and dilated cardiomyopathy. The inheritance of the mutation is autosomal recessive. As a causal gene, the desmoplakin gene (DSP) has so far been identified; it encodes an essential component of desmosomes, a cell-cell structure aimed at keeping cells attached to each other in tissues in which cells are often exposed to strong shear forces. Recently, familial cases of an autosomal dominant Carvajal syndrome were documented with a new feature: hypo/oligodontia. A mutation in the DSP gene was also evidenced in these latter cases. A patient was seen for cardiogenetic consultation at the University Hospital of Lyon with cardiac failure involving first degree atrioventricular block, complete left bundle branch block, non-compaction of the apex of the left ventricle and a dilated cardiomyopathy. A coronarography disclosed a complete thrombosis of the right coronary artery. At examination, he had also woolly hair, mild palmoplantar keratosis and missing teeth (essentially molars and premolars). His family history was uninformative. His DNA was screened for mutations in the DSP and plakoglobin genes but no mutation could be found. This case suggests that Carvajal syndrome with hypo/oligodontia is a heterogeneous condition in which genes other than DSP might be involved, although we cannot rule out a mutation in this gene consisting in a deletion of a single exon or a gene rearrangement

A Novel Alpha Cardiac Actin (<i>ACTC1</i>) Mutation Mapping to a Domain in Close Contact with Myosin Heavy Chain Leads to a Variety of Congenital Heart Defects, Arrhythmia and Possibly Midline Defects

<div><p>Background</p><p>A Lebanese Maronite family presented with 13 relatives affected by various congenital heart defects (mainly atrial septal defects), conduction tissue anomalies and midline defects. No mutations were found in <i>GATA4</i> and <i>NKX2-5</i>.</p><p>Methods and Results</p><p>A set of 399 poly(AC) markers was used to perform a linkage analysis which peaked at a 2.98 lod score on the long arm of chromosome 15. The haplotype analysis delineated a 7.7 meganucleotides genomic interval which included the alpha-cardiac actin gene (<i>ACTC1</i>) among 36 other protein coding genes. A heterozygous missense mutation was found (c.251T>C, p.(Met84Thr)) in the <i>ACTC1</i> gene which changed a methionine residue conserved up to yeast. This mutation was absent from 1000 genomes and exome variant server database but segregated perfectly in this family with the affection status. This mutation and 2 other <i>ACTC1</i> mutations (p.(Glu101Lys) and p.(Met125Val)) which result also in congenital heart defects are located in a region in close apposition to a myosin heavy chain head region by contrast to 3 other alpha-cardiac actin mutations (p.(Ala297Ser),p.(Asp313His) and p.(Arg314His)) which result in diverse cardiomyopathies and are located in a totally different interaction surface.</p><p>Conclusions</p><p>Alpha-cardiac actin mutations lead to congenital heart defects, cardiomyopathies and eventually midline defects. The consequence of an <i>ACTC1</i> mutation may in part be dependent on the interaction surface between actin and myosin.</p></div

Pedigree of the family with recurrent cardiopathies.

<p>Squares (males) and circle (females), crossed symbols (deceased), empty symbols (unaffected) and filled symbols (affected), arrow (proband). AF: atrial fibrillation; AR: aortic regurgitation; AS: aortic stenosis; ASD-OS: atrial septal defect ostium secundum type; LAH: left anterior hemiblock; LV: left ventricle; PAH: pulmonary artery hypertension; PS: pulmonary stenosis; RBBB: right bundle branch block; SB: sinus bradycardia; VSD: ventricular septal defect; WPW: Wolff Parkinson White.</p

Molecular representation of the PDB 4A7L complex, displaying an actin fiber (blue and green monomers, with ADP molecules in purple) with myosin heads (brown monomers).

<p>Actin and myosin amino acid numbers are according to human numbering <b>(A)</b> Backbone representation of an actin fiber in complex with 3 myosin heads, showing secondary structure elements. The backbone atoms of the 3 amino acids altered by mutations causing atrial septal defects (residues 84, 101, and 125) are shown by red spheres on every actin monomer. <b>(B)</b> Close up on the interaction between the region spanning residues 84, 101 and 125 of an F-actin monomer and a very close loop of the myosin head. The actin monomer is shown in green, the myosin head is shown in brown. The interatomic distances measured in the complex between residues 84, 101 and 125 and the myosin surface typically range from 3 to 10 Å. The 562–571 region of the myosin head makes numerous contacts with the surface of the actin filament, and interacts closely with residues 84, 101 and 125 on the surface of actin. <b>(C)</b> Close up showing one myosin head interacting with the region 84, 101, and 125 region of the actin monomer, and the 297, 313 and 314 region of an adjacent actin monomer. The 562–571 region of the myosin head closely interacts with residues whose mutation leads to atrial septal defects (84, 101, and 125, in red), whereas the 367–365 region (human numbering) of the same myosin head interacts directly with an adjacent actin monomer (residues 297, 313, 314, in green), whose mutation leads to cardiomyopathies. The orientation of the actin monomers in panel A and B is similar whereas the molecules in panel C have been rotated for a better view of the interaction with residues 297, 313, and 314.</p

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

International audienceThe etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 x), NKX2-5 (6 x), ZIC3 (3 x), MLPA (2 x) and ELN (4 x). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era

A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death.

BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is a genetically heterogeneous disease. One specific mutation in the MYBPC3 gene is highly prevalent in center east of France giving an opportunity to define the clinical profile of this specific mutation. METHODS: HCM probands were screened for mutation in the MYH7, MYBPC3, TNNT2 and TNNI3 genes. Carriers of the MYBPC3 IVS20-2A&gt;G mutation were genotyped with 8 microsatellites flanking this gene. The age of this MYBPC3 mutation was inferred with the software ESTIAGE. The age at first symptom, diagnosis, first complication, first severe complication and the rate of sudden death were compared between carriers of the IVS20-2 mutation (group A) and carriers of all other mutations (group B) using time to event curves and log rank test. RESULTS: Out of 107 HCM probands, 45 had a single heterozygous mutation in one of the 4 tested sarcomeric genes including 9 patients with the MYBPC3 IVS20-2A&gt;G mutation. The IVS20-2 mutation in these 9 patients and their 25 mutation carrier relatives was embedded in a common haplotype defined after genotyping 4 polymorphic markers on each side of the MYBPC3 gene. This result supports the hypothesis of a common ancestor. Furthermore, we evaluated that the mutation occurred about 47 generations ago, approximately at the 10th century.We then compared the clinical profile of the IVS20-2 mutation carriers (group A) and the carriers of all other mutations (group B). Age at onset of symptoms was similar in the 34 group A cases and the 73 group B cases but group A cases were diagnosed on average 15 years later (log rank test p = 0.022). Age of first complication and first severe complication was delayed in group A vs group B cases but the prevalence of sudden death and age at death was similar in both groups. CONCLUSION: A founder mutation arising at about the 10th century in the MYBPC3 gene accounts for 8.4% of all HCM in center east France and results in a cardiomyopathy starting late and evolving slowly but with an apparent risk of sudden death similar to other sarcomeric mutations

MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates.

Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates. Nat Genet 2015 Nov; 47(11):1260-3