Although the majority of melanomas develop due to cell damage caused by ultraviolet (UV) radiation exposure, susceptibility to melanoma is also influenced by genetics. For some families, inheritance of particular melanoma ‘risk’ genes can predispose to developing melanoma. These are grouped into ‘high’, ‘medium’ and ‘low’ penetrance genes, where penetrance reflects the likelihood of melanoma occurring over time in a person who carries the genetic mutation or polymorphism. Although no single mutation/variant guarantees disease development, the main impact is elevation of baseline melanoma risk, and it is likely that multiple low penetrance genes along with genetic and environmental modifiers combine to elicit a unique level of personal melanoma risk. In addition to cutaneous melanoma, some ‘melanoma’ predisposition genes have been linked to risk of other cancers. (By Dr. Jazlyn Read, http://jmg.bmj.com/content/early/2015/09/03/jmedgenet-2015-103150 )
Noonan syndrome with multiple lentigines, (NSML) formerly known as LEOPARD syndrome, has overlapping features with other RASopathies. Except for neurofibromatosis type 1, other disorders that result from dysregulated RAS/MAPK pathway are not known to be associated with neurogenic tumors. We identified four patients from three families with NSML, progressive neuropathy, enlarged nerves, massive burden of paraspinal neurofibromas and a mutation in the PTP catalytic domain of the PTPN11 gene (p.Thr468Met and p.Thr279Cys). Analysis of hypertrophic nerve did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes. Neurogenic tumors and hypertrophic neuropathy may be under-recognized manifestations of NSML that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation. (By Drs. Dusica Babovic-Vuksanovic and Erin Conboy, http://jmg.bmj.com/content/early/2015/09/02/jmedgenet-2015-103177 )
Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and distinctive brain MRI findings. Diagnosis and treatment of JS is challenging due to >28 associated genes and substantial clinical variability. This study provides a relatively unbiased view of the phenotypic range, genetic basis, and gene-phenotype associations in >500 individuals with JS. This information is crucial for diagnostic and carrier testing, medical monitoring for progressive complications, and interpretation of variants identified through genome-wide sequencing results. Understanding the genetic basis of JS is facilitating the development of gene-specific treatments. (By Dr. Dan Doherty, http://jmg.bmj.com/content/52/8/514 )
Primary gonadal failure is characterized by a lack of spontaneous pubertal development, primary amenorrhea or early menopause in females, and underdeveloped testis and azoospermia in males. Its genetic causes remain mostly unknown.
Variants of the minichromosome maintenance complex component 8 gene (MCM8) are significantly associated with early menopause. Mice lacking MCM8 are sterile. We sought to elucidate the genetic etiology of gonadal failure in two consanguineous families: family 1’s index case presented with primary amenorrhea and her brother had azoospermia; family 2’s five affected females had primary amenorrhea.
Using whole-exome sequencing, we identified two novel homozygous mutations in MCM8—splice (c.1954-1G>A) and frameshift (c.1469-1470insTA)—that segregated with the disease and were absent in 100 ethnically matched controls. The splice mutation (family 1) led to three different aberrant transcripts and a significant decrease in total MCM8 message. The frameshift mutation (family 2) predicted a premature stop codon. DNA-repair capabilities showed significantly increased chromosomal breakage.
Our findings indicate that MCM8 is crucial for gonadal development and maintenance and suggest its relevance in the larger context of reproductive lifespan in humans. (By Dr. Yardena Tenenbaum-Rakover, http://jmg.bmj.com/content/52/6/391 )
In March 2014 the International Gastric Cancer Linkage Consortium, a group of worldwide experts in the field of Hereditary Diffuse Gastric Cancer, held a consensus meeting in the Radboudumc in Nijmegen, The Netherlands. During this three-day meeting, the current evidence and world-wide experience for managing individuals with a family history of diffuse type gastric cancer was discussed. New criteria for CDH1 mutation testing, as well as updated endoscopy screening and surveillance protocols are described in the revised guideline. Additionally, the treatment of carriers of germline CDH1 mutations are extensively discussed including prophylactic surgery as well as nutritional and psychological needs. (By Dr. Ingrid Vogelaar, http://jmg.bmj.com/content/52/6/361 )
The IGCLC group
Hypertrophic Cardiomyopathy (HCM) is one of the most common inherited cardiac disorders with a prevalence of 1:500. It is characterized by unexplained left ventricular hypertrophy (from 13 mm to more than 35 mm) that develops in the absence of an underlying systemic condition or other cardiac disease. The most serious manifestations of HCM are sudden death and progressive heart failure. The majority of causal mutations are identified in genes encoding proteins of the sarcomere.
In this study we report the identification of a founder mutation in MYBPC3 gene in 20% of our Italian HCM patients. We found that the probability to develop the disease in mutation carriers is higher between 30 and 40 years of age, with a major risk if they are men. Probands carrying the founder mutation showed a higher prevalence of non-sustained ventricular tachycardia and ICD implantation with a significantly reduced survival after the fourth decade of life, when compared with patients negative for MYBPC3 mutations. (By Dr. Alessandra Rampazzo, http://jmg.bmj.com/content/52/5/338 )
Neurofibromatosis 2 is an inherited condition that predisposes to tumours of the nerve sheath (schwanomas) and brain lining (meningiomas). Most patients develop deafness and other handicaps that reduce life expectancy. In 1192 NF2 patients followed for an average of over 9 years, we confirmed that life expectancy was reduced when NF2 was diagnosed at a younger age, meningiomas were present, or certain particular kinds of genetic mutations caused the disease. We also showed that NF2 patients diagnosed in more recent decades had better survival than patients diagnosed earlier, reflecting improvements in diagnostic methods and treatment. (By Prof D Gareth Evans, http://jmg.bmj.com/content/early/2015/08/14/jmedgenet-2015-103290 )
Ciliopathies are diseases accounted for by alterations of cilia-dependent cellular functions. The clinical expression of ciliopathies is mostly limited to retina, kidney, brain, and bone. These organs can be affected individually or in multiple combinations, defining a wide spectrum of devastating overlapping syndromes. Studying 1,628 candidate individuals we identified homozygous IFT81 mutations in two individuals with kidney and bone anomalies and, retinal and brain lesions, respectively. The latter individual had additional biallelic mutations in PPT1, another gene for cerebro-retinal disease, questioning the respective contribution of PPT1 and IFT81 in his disease. Nevertheless, our finding suggests that IFT81 alteration causes ciliopathies. (By Drs. J. Halbritter, J. M. Rozet, I. Perrault and F. Hildebrandt, http://jmg.bmj.com/content/early/2015/08/14/jmedgenet-2014-102838 )
Up to 70% of patients with pheochromocytoma or paraganglioma (PPGL) harbor a somatic or germline mutation in one of the 22 genes described so far as related to the disease. However, patients with apparently sporadic PPGL tend to be excluded from genetic testing. This study should bring to an end years of controversy and debate, as it brings new evidence that highlights the need to recommend genetic testing for all patients with an apparently sporadic PPGL, regardless of the age of first PPGL diagnosis or the metastatic behavior. Of note, the study remarks benefits of identifying a somatic mutation for the patient and relatives. (By Dr. Maria Currás-Freixes, http://jmg.bmj.com/content/early/2015/08/12/jmedgenet-2015-103218 )
Mutations in the WAC gene have been recently reported in large screening cohorts of patients with intellectual disability or autism. We used whole exome sequencing to evaluate 6 patients with developmental delay, hypotonia, behavioral problems, constipation/feeding difficulties and common dysmorphic features including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. We identified 5 heterozygous loss-of-function WAC mutations; one mutation was found in two siblings but not detected in their healthy parents, strongly suggesting germline mosaicism. Our data highly suggest that WAC haploinsufficiency is responsible for the neurocognitive phenotype and facial dysmorphism associated with deletions encompassing 10p11.23 (By Marwan Shinawi, M.D., http://jmg.bmj.com/content/early/2015/08/11/jmedgenet-2015-103069 )