Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD.

Background-Hypertrophic cardiomyopathy (HCM) in infants and children is thought to be commonly associated with metabolic disorders and malformation syndromes. Familial disease caused by mutations in cardiac sarcomere protein genes, which accounts for most cases in adolescents and adults, is believed to be a very rare cause of HCM. Methods and Results-Seventy-nine consecutive patients diagnosed with HCM aged 13 years or younger underwent detailed clinical and genetic evaluation. The protein-coding sequences of 9 sarcomere protein genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC, and TNNC1), the genes encoding desmin (DES), and the ␥-2 subunit of AMP kinase (PRKAG2) were screened for mutations. A family history of HCM was present in 48 patients (60.8%). Forty-seven mutations (15 novel) were identified in 42 (53.2%) patients (5 patients had 2 mutations). The genes most commonly implicated were MYH7 (48.9%) and MYBPC3 (36.2%); mutations in TNNT2, ACTC, MYL3, and TNNI3 accounted for Ͻ5% of cases each. A total of 16.7% patients with sarcomeric mutations were diagnosed before 1 year of age. There were no differences in clinical and echocardiographic features between those children with sarcomere protein gene mutations and those without or between patients with 2 mutations and those with 1 or no mutations. Conclusions-This study shows that familial disease is common among infants and children with HCM and that, in most cases, disease is caused by mutations in cardiac sarcomere protein genes. The major implication is that all first-degree relatives of any child diagnosed with HCM should be offered screening. Furthermore, the finding that one sixth of patients with sarcomeric disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of familial HCM may have to be revised. (Circ Cardiovasc Genet. 2009;2:436-441.)

BackgroundClinical interpretation of the large number of rare variants identified by high throughput sequencing (HTS) technologies is challenging. The aim of this study was to explore the clinical implications of a HTS strategy for patients with hypertrophic cardiomyopathy (HCM) using a targeted HTS methodology and workflow developed for patients with a range of inherited cardiovascular diseases. By comparing the sequencing results with published findings and with sequence data from a large-scale exome sequencing screen of UK individuals, we sought to quantify the strength of the evidence supporting causality for detected candidate variants.Methods and results223 unrelated patients with HCM (46±15 years at diagnosis, 74% males) were studied. In order to analyse coding, intronic and regulatory regions of 41 cardiovascular genes, we used solution-based sequence capture followed by massive parallel resequencing on Illumina GAIIx. Average read-depth in the 2.1 Mb target region was 120. Rare (frequency<0.5%) non-synonymous, loss-of-function and splice-site variants were defined as candidates. Excluding titin, we identified 152 distinct candidate variants in sarcomeric or associated genes (89 novel) in 143 patients (64%). Four sarcomeric genes (MYH7, MYBPC3, TNNI3, TNNT2) showed an excess of rare single non-synonymous single-nucleotide polymorphisms (nsSNPs) in cases compared to controls. The estimated probability that a nsSNP in these genes is pathogenic varied between 57% and near certainty depending on the location. We detected an additional 94 candidate variants (73 novel) in desmosomal, and ion-channel genes in 96 patients (43%).ConclusionsThis study provides the first large-scale quantitative analysis of the prevalence of sarcomere protein gene variants in patients with HCM using HTS technology. Inclusion of other genes implicated in inherited cardiac disease identifies a large number of non-synonymous rare variants of unknown clinical significance.

Lamin A/C gene mutations can be found in severe forms of ARVC. Lamin A/C gene should be added to desmosomal genes when genetically testing patients with suspected ARVC, particularly when they also have ECG evidence for conduction disease.

Aim: To characterise and monitor abnormal fundus autofluorescence (AF) in patients with retinitis pigmentosa (RP) who have good visual acuity. Methods: 21 patients with a clinical diagnosis of RP were examined. All had rod-cone dystrophy (ISCEV standard electroretinograms (ERGs)), visual acuity of 6/9 or better, and manifested a parafoveal ring of high density fundus AF. Repeat AF imaging was performed after periods of between 2 years and 5 years in 12 patients. Pattern ERG (PERG) and multifocal ERG (mfERG) were performed in 20 cases. Visual fields (VF), photopic and scotopic fine matrix mapping and small field PERGs were performed in representative cases.Results: The rings of high density AF varied in size between patients (from 4˚-16˚diameter). MfERGs showed relative preservation over the central macular area, correlating with the size of AF ring and with PERG and psychophysical data. Progressive constriction of the AF ring was demonstrated at follow up in three patients. Serial PERG, mfERG, and VFs, performed in one of these cases, showed evidence of deterioration concordant with ring constriction. Conclusions: High density rings of AF, seen in some patients with RP with good visual acuity, demarcate areas of preserved central photopic function. MfERGs correlate with the area encircled by high density AF and the PERG data. The size of the ring of AF can show progressive constriction accompanied by increasing macular dysfunction.F undus autofluorescence (AF) imaging using a scanning laser ophthalmoscope is a non-invasive technique that has proved useful in numerous recent studies of inherited and acquired retinal disease in humans. 1-8 The major fluorophore (lipofuscin) accumulates in pigment epithelial cells and is derived from photoreceptor outer segments. Some patients with retinitis pigmentosa (RP) have abnormal fundus AF in the form of a parafoveal ring of high density that is not visible on routine ophthalmoscopic examination and that varies in size between patients. [9][10][11] The size of the high density ring correlates with the amplitude of the pattern electroretinogram (PERG) P50 component in patients with good visual acuity, 9 12 indicating differing degrees of cone system preservation over areas of central macula. Psychophysically determined sensitivity losses are consistent with the distribution of these high density annuli of fundus AF and with PERG data. Hyperautofluorescent areas represent a transition between abnormal paracentral and normal central cone system function 10 11 and correspond with the internal edge of visual field loss. The question of whether the ring is stationary or may represent a progressive phenomenon has not yet been satisfactorily addressed.Multifocal ERGs (mfERG) are mathematically derived cone driven responses associated with localised retinal areas across the posterior pole. Stimulus elements within a hexagonal array are activated according to a rapid pseudo-random binary sequence (m-sequence) and the resultant continuous ERG signal is cross correlated with the area s...