Genetics of atrioventricular canal defects

Atrioventricular canal defect (AVCD) represents a quite common congenital heart defect (CHD) accounting for 7.4% of all cardiac malformations. AVCD is a very heterogeneous malformation that can occur as a phenotypical cardiac aspect in the context of different genetic syndromes but also as an isolated, non-syndromic cardiac defect. AVCD has also been described in several pedigrees suggesting a pattern of familiar recurrence. Targeted Next Generation Sequencing (NGS) techniques are proved to be a powerful tool to establish the molecular heterogeneity of AVCD. Given the complexity of cardiac embryology, it is not surprising that multiple genes deeply implicated in cardiogenesis have been described mutated in patients with AVCD. This review attempts to examine the recent advances in understanding the molecular basis of this complex CHD in the setting of genetic syndromes or in non-syndromic patients

Obituary of Dr. Angelo Di George

[No abstract available

22q11.2 Deletion Syndrome. Impact of Genetics in the Treatment of Conotruncal Heart Defects

Congenital heart diseases represent one of the hallmarks of 22q11.2 deletion syndrome. In particular, conotruncal heart defects are the most frequent cardiac malformations and are often associated with other specific additional cardiovascular anomalies. These findings, together with extracardiac manifestations, may affect perioperative management and influence clinical and surgical outcome. Over the past decades, advances in genetic and clinical diagnosis and surgical treatment have led to increased survival of these patients and to progressive improvements in postoperative outcome. Several studies have investigated long-term follow-up and results of cardiac surgery in this syndrome. The aim of our review is to examine the current literature data regarding cardiac outcome and surgical prognosis of patients with 22q11.2 deletion syndrome. We thoroughly evaluate the most frequent conotruncal heart defects associated with this syndrome, such as tetralogy of Fallot, pulmonary atresia with major aortopulmonary collateral arteries, aortic arch interruption, and truncus arteriosus, highlighting the impact of genetic aspects, comorbidities, and anatomical features on cardiac surgical treatment

A computational search for box C/D snoRNA genes in the Drosophila melanogaster genome

Abstract Motivation: In eukaryotes, the family of non-coding RNA genes includes a number of genes encoding small nucleolar RNAs (mainly C/D and H/ACA snoRNAs), which act as guides in the maturation or post-transcriptional modifications of target RNA molecules. Since in Drosophila melanogaster (Dm) only few examples of snoRNAs have been identified so far by cDNA libraries screening, integration of the molecular data with in silico identification of these types of genes could throw light on their organization in the Dm genome. Results: We have performed a computational screening of the Dm genome for C/D snoRNA genes, followed by experimental validation of the putative candidates. Few of the 26 confirmed snoRNAs had been recognized by cDNA library analysis. Organization of the Dm genome was also found to be more variegated than previously suspected, with snoRNA genes nested in both the introns and exons of protein-coding genes. This finding suggests that the presence of additional mechanisms of snoRNA biogenesis based on the alternative production of overlapping mRNA/snoRNA molecules. Availability: Additional information is available at http://www.bioinformatica.unito.it/bioinformatics/snoRNA

Leopard syndrome

LEOPARD syndrome (LS, OMIM 151100) is a rare multiple congenital anomalies condition, mainly characterized by skin, facial and cardiac anomalies. LEOPARD is an acronym for the major features of this disorder, including multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness. About 200 patients have been reported worldwide but the real incidence of LS has not been assessed. Facial dysmorphism includes ocular hypertelorism, palpebral ptosis and low-set ears. Stature is usually below the 25th centile. Cardiac defects, in particular hypertrophic cardiomyopathy mostly involving the left ventricle, and ECG anomalies are common. The lentigines may be congenital, although more frequently manifest by the age of 4–5 years and increase throughout puberty. Additional common features are café-au-lait spots (CLS), chest anomalies, cryptorchidism, delayed puberty, hypotonia, mild developmental delay, sensorineural deafness and learning difficulties. In about 85% of the cases, a heterozygous missense mutation is detected in exons 7, 12 or 13 of the PTPN11 gene. Recently, missense mutations in the RAF1 gene have been found in two out of six PTPN11-negative LS patients. Mutation analysis can be carried out on blood, chorionic villi and amniotic fluid samples. LS is largely overlapping Noonan syndrome and, during childhood, Neurofibromatosis type 1-Noonan syndrome. Diagnostic clues of LS are multiple lentigines and CLS, hypertrophic cardiomyopathy and deafness. Mutation-based differential diagnosis in patients with borderline clinical manifestations is warranted. LS is an autosomal dominant condition, with full penetrance and variable expressivity. If one parent is affected, a 50% recurrence risk is appropriate. LS should be suspected in foetuses with severe cardiac hypertrophy and prenatal DNA test may be performed. Clinical management should address growth and motor development and congenital anomalies, in particular cardiac defects that should be monitored annually. Hypertrophic cardiomyopathy needs careful risk assessment and prophylaxis against sudden death in patients at risk. Hearing should be evaluated annually until adulthood. With the only exception of ventricular hypertrophy, adults with LS do not require special medical care and long-term prognosis is favourable

Mutational analysis of the PITX2 coding region revealed no common cause for transposition of the great arteries (dTGA)

BACKGROUND: PITX2 is a bicoid-related homeodomain transcription factor that plays an important role in asymmetric cardiogenesis. Loss of function experiments in mice cause severe heart malformations, including transposition of the great arteries (TGA). TGA accounts for 5–7% of all congenital heart diseases affecting 0.2 per 1000 live births, thereby representing the most frequent cyanotic heart defect diagnosed in the neonatal period. METHODS: To address whether altered PITX2 function could also contribute to the formation of dTGA in humans, we screened 96 patients with dTGA by means of dHPLC and direct sequencing for mutations within the PITX2 gene. RESULTS: Several SNPs could be detected, but no stop or frame shift mutation. In particular, we found seven intronic and UTR variants, two silent mutations and two polymorphisms within the coding region. CONCLUSION: As most sequence variants were also found in controls we conclude that mutations in PITX2 are not a common cause of dTGA