This new heart-hand syndrome should therefore be considered as a new kind of laminopathy. As part of laminopathies with heart involvement, patients presenting with this phenotype and their relatives are at risk for developing sudden cardiac death and should beneficiate from appropriate LMNA genetic diagnosis.

In conclusion, we present a novel approach to a phenotype-driven diagnostic process of genome scale sequencing data that harnesses the sensitivity of these approaches while restricting the analysis to genes relevant to clinical presentation in patient.Genet Med 18 11, 1102-1110.

Langer-Giedion syndrome (LGS) is a contiguous gene syndrome caused by a hemizygous deletion on chromosome 8q23.3-q24.11 involving TRPS1 and EXT1 genes. We report on a girl with LGS phenotype and a 7.5 Mb interstitial deletion at chromosome 8q23.3-q24.13. Array-comparative genomic hybridization (a-CGH) revealed a deletion encompassing only the EXT1 and not the TRPS1 gene. Even though the deletion of TRPS1 and EXT1 genes is responsible for craniofacial and skeletal features of LGS, there have been previous reports of patients with LGS phenotype and 8q24 deletions leaving the TRPS1 gene intact. To our knowledge, this is the third such case. Our patient differs from previously reported LGS patients without TRPS1 gene deletion in that she has the typical LGS facial dysmorphism and skeletal abnormalities. However, the girl is of normal height and has only a mild developmental delay. Additionally, she has dyslalia and premature adrenarche classified as Tanner stage 3 premature pubarche which have not yet been described as features of LGS. We examine the molecular breakpoints and phenotypes of our patient and previously reported cases.

Idiopathic recurrent spontaneous abortion (IRSA) has been associated with abnormalities in the remodelling of endometrial extracellular matrix, as well as aberrant matrix metalloproteinase (MMP) gene expression in endometrium of IRSA women and chorionic villi of IRSA concept. This study investigated the association of five functional MMP gene promoter polymorphisms (MMP1 -1607 1G/2G, MMP2 -735 C/T, MMP2 -1306 C/T, MMP3 -1612 5A/6A and MMP9 -1562 C/T) with IRSA. A total of 149 couples with at least three consecutive IRSA and 149 fertile couples were included in a case-control study. Genotype analysis was performed using PCR restriction fragment length polymorphism. Statistically significant differences were found in distributions of MMP2 -735 CT (chi-squared 10.21, P=0.006; OR 2.15, 95% CI 1.34-3.45, P=0.001), and MMP9 -1562 CC (chi-squared 9.06, P=0.010; OR 2.21, 95% CI 1.30-3.80, P=0.004) between IRSA women and controls. Combined analysis of MMP gene polymorphisms did not increase their predictive value. There were no statistically significant differences in genotype and allele frequencies of any polymorphism between IRSA men and controls. MMP2 -735 C/T and MMP9 -1562 C/T functional gene polymorphisms might be associated with an increased risk of IRSA in women. Considering the insufficient knowledge on genetic contribution to pregnancy loss, studies on genetic causes of idiopathic recurrent spontaneous abortion (IRSA) are of great importance. Development of a histologically and functionally normal endometrium is critical for subsequent endometrial decidualization, receptivity and implantation. The proper communication and interaction between maternal decidual cells and the embryo is essential for the establishment of a functional fetal-maternal interface. IRSA has been associated with abnormalities in the remodelling of endometrial extracellular matrix, as well as aberrant matrix metalloproteinase (MMP) gene expression in endometrium of IRSA women and chorionic villi of IRSA concepti. The aim of this study was to investigate the association of five functional MMP gene promoter polymorphisms with IRSA. A total of 149 couples with at least three consecutive IRSA and 149 fertile couples were included in a case-control study. Genotype analysis was performed using polymerase chain reaction and restriction fragment length polymorphism. Statistically significant differences were found in distribution of MMP2 -735 CT and MMP9 -1562 CC genotypes between IRSA and control women. Combined analysis of MMP gene polymorphisms did not increase their predictive value. There were no statistically significant differences in distribution of genotype and allele frequencies of any polymorphism between IRSA men and controls. Our results demonstrate that MMP2 -735 C/T and MMP9 -1562 C/T functional gene polymorphisms might be associated with an increased risk of IRSA in women.

We identified a family with 10 affected members in four generations suffering from adult-onset progressive sinoatrial and atrioventricular conduction disease, sudden death due to ventricular tachyarrhythmia, dilated cardiomyopathy, and a unique type of brachydactyly with mild hand involvement (short distal, middle, proximal phalanges and clinodactyly) and more severe foot involvement (short distal, proximal phalanges and metatarsal bones, short or absent middle phalanges, terminal symphalangism, duplication of the bases of the second metatarsals, extra ossicles, and syndactyly). The phenotype differences from other reported genetic abnormalities and linkage exclusion of Holt-Oram syndrome, ulnar-mammary syndrome, brachydactyly type B or Robinow syndrome, and cardiac conduction disease or Brugada syndrome loci suggest that we report on a new hereditary heart-hand syndrome.