Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin.

We have identified nonsense mutations in the gene CDSN (encoding corneodesmosin) in three families suffering from hypotrichosis simplex of the scalp (HSS; OMIM 146520). CDSN, a glycoprotein expressed in the epidermis and inner root sheath (IRS) of hair follicles, is a keratinocyte adhesion molecule. Truncated CDSN aggregates were detected in the superficial dermis and at the periphery of hair follicles. Our findings suggest that CDSN is important in normal scalp hair physiology.

Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.

BACKGROUND: The hyperpolarization-activated nucleotide-gated channel--HCN4 plays a major role in the diastolic depolarization of sinus atrial node cells. Mutant HCN4 channels have been found to be associated with inherited sinus bradycardia. METHODS AND RESULTS: Sixteen members of a family with sinus bradycardia were evaluated. Evaluation included a clinical questionnaire, 12-lead ECGs, Holter monitoring, echocardiography, and treadmill exercise testing. Eight family members (5 males) were classified as affected. All affected family members were asymptomatic with normal exercise capacity during long-term follow-up. Electrophysiological testing performed on 2 affected family members confirmed significant isolated sinus node dysfunction. Segregation analysis suggested autosomal-dominant inheritance. Direct sequencing of the exons encoding HCN4 revealed a missense mutation, G480R, in the ion channel pore domain in all affected family members. Function analysis, including expression of HCN4 wild-type and G480R in Xenopus oocytes and human embryonic kidney 293 cells, revealed that mutant channels were activated at more negative voltages compared with wild-type channels. Synthesis and expression of the wild-type and mutant HCN4 channel on the plasma membrane tested in human embryonic kidney 293 cells using biotinylation and Western blot analysis demonstrated a reduction in synthesis and a trafficking defect in mutant compared with wild-type channels. CONCLUSIONS: We describe an inherited, autosomal-dominant form of sinus node dysfunction caused by a missense mutation in the HCN4 ion channel pore. Despite its critical location, this mutation carries a favorable prognosis without the need for pacemaker implantation during long-term follow-up.

Expanding preconception carrier screening for the Jewish population using high throughput microfluidics technology and next generation sequencing.

BACKGROUND: Genetic screening to identify carriers of autosomal recessive diseases has become an integral part of routine prenatal care. In spite of the rapid growth of known mutations, most current screening programs include only a small subset of these mutations, and are performed using diverse molecular techniques, which are generally labor-intensive and time consuming. We examine the implementation of the combined high-throughput technologies of specific target amplification and next generation sequencing (NGS), for expanding the carrier screening program in the Israeli Jewish population as a test case. METHODS: We compiled a panel of 370 germline mutations, causing 120 disorders, previously identified in affected Jewish individuals from different ethnicities. This mutation panel was simultaneously captured in 48 samples using a multiplex PCR-based microfluidics approach followed by NGS, thereby performing 17,760 individual assays in a single experiment. RESULTS: The sensitivity (measured with depth of at least 50×) and specificity of the target capture was 98 and 95 % respectively, leaving minimal rate of inconclusive tests per sample tested. 97 % of the targeted mutations present in the samples were correctly identified and validated. CONCLUSION: Our methodology was shown to successfully combine multiplexing of target specific primers, samples indexing and NGS technology for population genetic screens. Moreover, it's relatively ease of use and flexibility of updating the targets screened, makes it highly suitable for clinical implementation. This protocol was demonstrated in pre-conceptional screening for pan-Jewish individuals, but can be applied to any other population or different sets of mutations.

A missense mutation in the CASQ2 gene is associated with autosomal-recessive catecholamine-induced polymorphic ventricular tachycardia.

Catecholamine-induced polymorphic ventricular tachycardia (CPVT), a rare disease that occurs in subjects without obvious organic heart disease, is characterized by episodes of syncope, seizures, or sudden death in response to physiologic or emotional stress. This report reviews evidence that a missense mutation in the CASQ2 gene is associated with autosomal-recessive CPVT.

Genetic ideology of dilated cardiompathy.

Familial cardiomyopathies represent a substantial portion of idiopathic dilated cardiomyopathy in clinical practice. Diversity of clinical presentations and variability in penetrance lead to under-recognition of this disease entity as an inherited disorder. The mechanisms by which mutations in different genes perturb cardiac function and lead to pathologic remodeling help us understand the molecular pathways in disease pathogenesis and define the potential targets for therapeutic interventions. Appreciating when DCM is inherited might spare unnecessary diagnostic efforts and, instead, help give appropriate attention to the timely detection of subclinically affected family members. Establishing preventive therapy in asymptomatic family members showing early signs of cardiac dysfunction might prevent death and slow down progression to end-stage heart failure.

A novel form of familial bidirectional ventricular tachycardia.

We evaluated a family with 30 members, 3 of whom had incessant polymorphous and bidirectional ventricular tachycardia (VT) that was electrocardiographically similar to that described in other familial polymorphic VT series; the VT was unrelated to exercise and asymptomatic. More subtle, but morphologically similar, ventricular arrhythmias were detected in 3 other family members. Genes related to intracellular calcium transport were specifically excluded.

Autosomal recessive catecholamine-induced polymorphic ventricular tachycardia.

Catecholamine-induced polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures or sudden death, in response to physical activity or emotional stress, and affects mainly young children with morphologically normal hearts. An autosomal recessive form of the disorder in seven families from a Bedouin tribe in the north of Israel was recently described by the authors, and the disease-causing gene was mapped to chromosome 1p13-1p21. Direct sequencing of calsequestrin 2 (CASQ2), a candidate gene from within the linkage interval, revealed a negatively charged aspartic acid change to a positively charged histidine at position 307 of the protein. CASQ2 serves as the major calcium reservoir within cardiac myocytes. This mutation occurs in a highly conserved residue of the protein. The implication of the calcium release cascade in this disease may lead to a better understanding of the pathophysiological events underlying ventricular tachycardia, and to the use of drugs directly involved in intracellular calcium control for the treatment of the PVT patients.

A novel titin mutation in adult-onset familial dilated cardiomyopathy.

Familial dilated cardiomyopathy is a major cause of advanced heart failure and heart transplantation. In most families, the disease-causing mutation is unknown, and relatives should therefore undergo periodic screening to facilitate early diagnosis and therapy. In the present study, we describe a novel titin truncation mutation causing adult-onset familial dilated cardiomyopathy in an Israeli Arab family. The family members underwent physical examination, electrocardiography, and Doppler echocardiography. Linkage to candidate loci was performed, followed by gene sequencing. We identified 13 clinically affected family members (8 men and 5 women, mean age 47 ± 12 years). Compared with their healthy first-degree relatives, the affected relatives had a larger end-diastolic left ventricular dimension (60 ± 10 vs 49 ± 4 mm, p <0.001), lower ejection fraction (43 ± 11% vs 60 ± 6%, p <0.001), and markedly higher end-systolic volume indexes but no difference in wall thickness or diastolic function. The linkage studies or direct sequencing excluded LMNA, MYH7, TNNT2, TNNI3, SCN5A, DES, SGCD, ACTC, PLN, and MYH6 but established linkage to the TTN locus at chromosome 2q31, yielding a maximum (2-point) LOD score of 3.44. Sequence analysis identified an insertion (c.58880insA), causing protein truncation after 19,628 amino acids (p.S19628IfsX1). No founder effect was found among the Israeli Arabs. In conclusion, titin is a giant protein with a key role in sarcomere assembly, force transmission, and maintenance of resting tension. Although some mutations result in skeletal myopathy, others cause isolated, maturity-onset cardiomyopathy.

A missense mutation in CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.

Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is characterized by episodes of syncope, seizures or sudden death, in response to physical activity or emotional stress, and affects mainly young children with morphologically normal hearts. We have recently described an autosomal recessive form of the disorder in seven families from a Bedouin tribe in the north of Israel, and mapped the disease-causing gene to chromosome 1p13-1p21. Direct sequencing of the calsequestrin 2 (CASQ2), a candidate gene from within the linkage interval, revealed a negatively charged aspartic acid change to a positively charged histidine at position 307 of the protein. CASQ2 serves as the major calcium reservoir within cardiac myocytes. This mutation occurs in a highly conserved residue of the protein. The implication of the calcium release cascade in this disease, may lead to a better understanding of the pathophysiologic events underlying ventricular tachycardia, and to the use of drugs directly involved in intracellular calcium control for the treatment of the CPVT patients.

A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family.

In an inbred Iraqi Jewish family, we have studied three siblings with presenile cataract first noticed between the ages of 20 and 51 years and segregating in an autosomal recessive mode. Using microsatellite repeat markers in close proximity to 25 genes and loci previously associated with congenital cataracts in humans and mice, we identified five markers on chromosome 19q that cosegregated with the disease. Sequencing of LIM2, one of two candidate genes in this region, revealed a homozygous T-->G change resulting in a phenylalanine-to-valine substitution at position 105 of the protein. To our knowledge, this constitutes the first report, in humans, of cataract formation associated with a mutation in LIM2. Studies of late-onset single-gene cataracts may provide insight into the pathogenesis of the more common age-related cataracts.

Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive inherited neurological disorder characterized by macrocephaly, deterioration in motor functions and cerebellar ataxia. In Israel the disease is found in an increased frequency among Libyan Jews. The disease is caused by mutations in the MLC1 gene, which encodes a putative CNS membrane transporter. We describe three novel mutations (p.G59E, p.P92S, and 134_136insC) in seven MLC families. One of these mutations, p.G59E, was found in the vast majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the p.G59E mutation, revealed a carrier rate of 1/40 compared with an expected carrier rate of 1/81. Several explanations could account for this difference the most likely one is an admixture of the Libyan Jewish population.