Clinical Laboratories Collaborate to Resolve Differences in Variant Interpretations Submitted to ClinVar

Purpose Data sharing through ClinVar offers a unique opportunity to identify interpretation differences between laboratories. As part of a ClinGen initiative, four clinical laboratories (Ambry, GeneDx, Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory) collaborated to identify the basis of interpretation differences and to investigate if data sharing and reassessment resolves interpretation differences by analyzing a subset of variants. Methods: ClinVar variants with submissions from at least two of the four participating laboratories were compared. For a subset of identified differences, laboratories documented the basis for discordance, shared internal data, independently reassessed with the ACMG-AMP guidelines, and then compared interpretations. Results: 6,169 variants in ClinVar were interpreted by at least two of the participating laboratories, of which 88.3% were initially concordant. Laboratories reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing. 12.8% (31) of reassessed variants remain discordant due to differences in application of the ACMG-AMP guidelines. Conclusion: Participating laboratories increased their overall concordance from 88.3% to 91.7%, indicating that sharing variant interpretations in ClinVar, allowing identification of differences and motivation to resolve those differences, is critical to move toward more consistent variant interpretations

ACMG clinical laboratory standards for next-generation sequencing

Next-generation sequencing technologies have been and continue to be deployed in clinical laboratories, enabling rapid transformations in genomic medicine. These technologies have reduced the cost of large-scale sequencing by several orders of magnitude, and continuous advances are being made. It is now feasible to analyze an individual's near-complete exome or genome to assist in the diagnosis of a wide array of clinical scenarios. Next-generation sequencing technologies are also facilitating further advances in therapeutic decision making and disease prediction for at-risk patients. However, with rapid advances come additional challenges involving the clinical validation and use of these constantly evolving technologies and platforms in clinical laboratories. To assist clinical laboratories with the validation of next-generation sequencing methods and platforms, the ongoing monitoring of next-generation sequencing testing to ensure quality results, and the interpretation and reporting of variants found using these technologies, the American College of Medical Genetics and Genomics has developed the following professional standards and guidelines

Findings from the Peutz-Jeghers Syndrome Registry of Uruguay

Background: Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients. Methods: Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed. Results and discussion: 25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000. Conclusion: The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation

Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome.

PurposeNevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal-dominant disorder characterized by multiple basal cell carcinomas, jaw cysts, palmar/plantar pits, calcification of the falx cerebri, and spine and rib anomalies. NBCCS is due to mutations in PTCH1, the human homologue of the Drosophila segment polarity gene patched. Mutations are detected in approximately 60% to 85% of individuals tested by sequencing of PTCH1; therefore, clinical examination and x-rays remain important in diagnosis of NBCCS.MethodsWe studied 82 NBCCS patients and 38 of their unaffected siblings at the NIH between 1985 and 1994. Chest, rib, spine, skull, hand and foot x-rays, brain MRI or CT, and pelvic ultrasound (in females) were obtained in the affected individuals and compared to their unaffected relatives.ResultsThe following features were significantly more frequent in those with NBCCS: calcification of the falx cerebri, the most frequent radiological feature, was present in 79% of patients > 20 years and in 37% <20 years, calcification of the tentorium cerebellum was present in 20%, bridging of the sella in 68%, and abnormal frontal sinus aeration in 18% of affected individuals. Bifid ribs most often involving the third, fourth, and fifth ribs were seen in 26%; splayed, fused, and misshapen ribs in a further 16%, and widened ends of clavicles in 12%. Spine X-rays revealed calcification of the nuchal ligament in 18%, fusion of vertebrae in 10%, and hemivertebrae in 15%. Flame-shaped lucencies of the metacarpals and/or phalanges were present in 30%, modeling deformities of the phalanges in 14%, and polydactyly of the feet in 4%. The frequency of scoliosis, cervical ribs, absent or rudimentary ribs, spina bifida occulta, or short 4th metacarpal was not higher in the affected individuals as compared to their unaffected relatives. Except for falx calcification, the frequency of radiological manifestations was similar in different age groups. Cranial CT or MRI in 42 affected individuals revealed asymmetric or dilated ventricles in 24%, cerebral atrophy in 10%, cavum septum pellucidum in 19%, dysgenesis or agenesis of the corpus callosum in 10%, and meningioma in 5%. Ovarian fibromas were detected in 17% of females.ConclusionsThis study reports the varied radiological manifestations of NBCCS. In the absence of major features such as basal cell carcinomas, jaw cysts, or falx calcification, which is often not evident until the teen years, other radiological manifestations of the disorder can permit early diagnosis of NBCCS in childhood. This will allow optimum surveillance for medulloblastoma and other neoplasms (cardiac fibromas and basal cell carcinomas) associated with NBCCS

Clinical Features In Children With Nevoid Basal Cell Carcinoma Syndrome.• 863

Nevoid Basal Cell Carcinoma Syndrome (NBCC), an autosomal dominant disorder linked to 9q22.3-q31, is characterized by multiple basal cell carcinomas(BCCs), keratocysts of the jaw, palmar/plantar pits and calcification of the falx cerebri. Twenty-six families including 105 persons with NBCC participated in a linkage and clinical study at the NIH since 1985. Of these, 30 were children aged from 4 mo. to 19 yr. (mean 11.3 yr., M:F ratio 1:1). On comparing the frequency of the major clinical features, 55% of children and 91% of adults had at least one BCC. The number of BCCs ranged from 1- > 1000 (median 1) & 1-500 (median 31.5) respectively. Jaw cysts occurred in 60% of children and 81% of adults, the no. of cysts ranging from 1-6 (median 3) and 1-28 (median 5) respectively. Lifetable analysis of adults and children indicated that 50% developed their first BCCs by the age of 21.5 yr. and their first jaw cyst by the age of 15 yr. Palmar/plantar pits were observed at approximately the same frequency in children (89%) and adults (87%). Calcification of the falx cerebri was seen in 37% children and 78% adults. On comparison with their unaffected siblings (N=25) features seen exclusively in affected children were frontal bossing (44.8%), hypertelorism (38.5%), Sprengels deformity (17.9%), pectus deformity (14.8%), and cleft lip/palate(6.6%). Sixty percent of affected and 8% of unaffected children had macrocephaly (HC > 2SD)(p <0.01). Radiological features seen exclusively in affected children were calcification of the tentorium cerebellum (13%), bifid ribs (29%), hemivertebrae (9%), fusion of the vertebral bodies (9%), and flame shaped lucencies of the hand (16%). This study indicates that many of the major features (jaw cysts, BCCS, and falx calcification) develop over time. Therefore a diagnosis can be established in young persons by the presence of palmar pits, and evaluation of the above mentioned clinical and radiological features of NBCC