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Germline variants in CDH1 are associated with elevated risks of diffuse gastric cancer and lobular breast cancer. It is uncertain whether there is an increased risk of colorectal neoplasia.This was a retrospective analysis of colonoscopy outcomes in patients with germline CDH1 pathogenic/likely pathogenic variants.Eighty-five patients were included with a mean age of 46.9 years. Initial colonoscopy found adenomatous polyps in 30 patients (35.3%), including advanced adenomas in 9 (10.6%). No colorectal cancers were identified on index or subsequent colonoscopies (when available).CDH1 carriers have colorectal neoplasia identified at similar rates as in the general population. Despite potential difficulties after gastrectomy, colorectal cancer screening remains important in this population.

A family with three affected males and a second family with a single affected male with intellectual disability, microcephaly, ophthalmoplegia, deafness, and Involuntary limb movements were reported by Schimke and Associates in 1984. The affected males with Schimke X-linked intellectual disability (XLID) syndrome (OMIM# 312840) had a similar facial appearance with deep-set eyes, downslanting palpebral fissures, hypotelorism, narrow nose and alae nasi, cupped ears and spacing of the teeth. Two mothers had mild hearing loss but no other manifestations of the disorder. The authors considered the disorder to be distinctive and likely X-linked. Whole genome sequencing in the single affected male available and the three carrier females from one of the families with Schimke XLID syndrome identified a 2 bp deletion in the BCAP31 gene. During the past decade, pathogenic alterations of the BCAP31 gene have been associated with deafness, dystonia, and central hypomyelination, an XLID condition given the eponym DDCH syndrome. A comparison of clinical findings in Schimke XLID syndrome and DDCH syndrome shows them to be the same clinical entity. The BCAP31 protein functions in endoplasmic reticulum-associated degradation to promote ubiquitination and destruction of misfolded proteins.

Importance Performing DNA genetic testing (DGT) for hereditary cancer genes is now a well-accepted clinical practice; however, the interpretation of DNA variation remains a challenge for laboratories and clinicians. Adding RNA genetic testing (RGT) enhances DGT by clarifying the clinical actionability of hereditary cancer gene variants, thus improving clinicians’ ability to accurately apply strategies for cancer risk reduction and treatment. Objective To evaluate whether RGT is associated with improvement in the diagnostic outcome of DGT and in the delivery of personalized cancer risk management for patients with hereditary cancer predisposition. Design, Setting, and Participants Diagnostic study in which patients and/or families with inconclusive variants detected by DGT in genes associated with hereditary breast and ovarian cancer, Lynch syndrome, and hereditary diffuse gastric cancer sent blood samples for RGT from March 2016 to April 2018. Clinicians who ordered genetic testing and received a reclassification report for these variants were surveyed to assess whether RGT-related variant reclassifications changed clinical management of these patients. To quantify the potential number of tested individuals who could benefit from RGT, a cohort of 307 812 patients who underwent DGT for hereditary cancer were separately queried to identify variants predicted to affect splicing. Data analysis was conducted from March 2016 and September 2018. Main Outcomes and Measures Variant reclassification outcomes following RGT, clinical management changes associated with RGT-related variant reclassifications, and the proportion of patients who would likely be affected by a concurrent DGT and RGT multigene panel testing approach. Results In total, 93 if 909 eligible families (10.2%) submitted samples for RGT. Evidence from RGT clarified the interpretation of 49 of 56 inconclusive cases (88%) studied; 26 (47%) were reclassified as clinically actionable and 23 (41%) were clarified as benign. Variant reclassifications based on RGT results changed clinical management recommendations for 8 of 18 patients (44%) and 14 of 18 families (78%), based on responses from 18 of 45 clinicians (40%) surveyed. A total of 7265 of 307 812 patients who underwent DGT had likely pathogenic variants or variants of uncertain significance potentially affecting splicing, indicating that approximately 1 in 43 individuals could benefit from RGT. Conclusions and Relevance In this diagnostic study, conducting RNA testing resolved a substantial proportion of variants of uncertain significance in a cohort of individuals previously tested for cancer predisposition by DGT. Performing RGT might change the diagnostic outcome of at least 1 in 43 patients if performed in all individuals undergoing genetic evaluation for hereditary cancer.

Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome with lifetime CRC risks of up to 70%.1 Conventionally, CRC specimens are screened for LS postoperatively but preoperative diagnosis of LS could impact decisions, such as the extent of resection and the need for additional risk-reducing surgeries for uterine and ovarian cancers. Few studies have addressed this issue2-5 and surveys indicate that most gastroenterologists are unsure that LS can be screened for preoperatively.6 We compared the yield of preoperative versus postoperative screening of LS by immunohistochemistry (IHC) and microsatellite instability (MSI) in unselected patients with newly diagnosed CRC who underwent testing under real-life laboratory conditions to mimic clinical practice.

Background Historically, three founder mutations in the BRCA1/2 (OMIM 113705; OMIM 600185) genes have been the focus of cancer risks within the Ashkenazi Jewish (AJ) population. However, there are several additional mutations associated with increased susceptibility to cancer in individuals of AJ ancestry. Methods We report three patients who exemplify the need to keep these additional founder mutations in mind when pursuing hereditary cancer genetic testing of individuals in this population. All gene sequences in this paper were aligned to reference sequences based on human genome build GRCh37/UCSC hg19. Results review of the literature discusses that the combined risk is 12.36%–20.83% forhaving 1 of the 10 hereditary cancer AJ founder mutations in the BRCA1, BRCA2, CHEK2 (OMIM 604373), APC (OMIM 611731), MSH2 (OMIM 609309), MSH6 (OMIM 600678), and GREM1 (OMIM 603054) genes for individuals of AJ ancestry. Conclusion We recommend testing for all 10 of these AJ founder cancer susceptibility mutations for individuals within this population as standard screening in order to ensure appropriate cancer risk management and cascade testing.

We have identified a family segregating von Hippel-Lindau (VHL) disease with a previously unreported T547A mutation in exon 1 of the VHL gene that causes a Tyr112 to Asn missense alteration in the protein. The mutation was identified by nucleotide sequencing and confirmed by restriction enzyme digestion. The mutation cosegregated with the disease in all five tested affected individuals from the extended family. The family consists of more than 100 at-risk individuals over seven generations. To date, we have identified 13 affected individuals of whom seven have had renal cell carcinoma and one has had a pheochromocytoma. No other case of a neuroendocrine tumor of the pancreas or adrenal gland (pheochromocytoma) was found or recognized retrospectively. Other manifestations in this family include retinal angioma and hemangioblastoma of the central nervous system. We also found the T547A mutation in three asymptomatic members of the family, ages 12, 19, and 20. Another mutation, T547C, which causes Tyr112 to His, has been seen at the same position and has been associated with VHL type 2A (pheochromocytoma, but no renal cell carcinoma) in two families with a total of 22 affected individuals [Chen F, Slife L, Kishida T, Mulvihill J, Tisherman SE, Zbar B, 1996: J Med Genet 33:716-717]. Thus, different amino acid changes at the same position can cause very distinct clinical phenotypes. It will be interesting to elucidate the functional differences that underlie the different phenotypes.

A child with Moebius syndrome and minor extremity anomalies is described. Her father had a transverse defect of the right arm with absence of the radius and ulna just below the elbow but no cranial nerve dysfunction. While possibly unrelated, review of the literature suggests these anomalies may both be part of a single broad spectrum syndrome, perhaps dominantly inherited.

Familial paraganglioma/pheochromocytoma (PGL/PCC) is genetically heterogenous with mutations in three of the four subunits of the heterotetrameric mitochondrial complex II enzyme succinate dehydrogenase (SDH) being causally responsible for the majority of cases. In addition to PGL/PCC an array of non-paraganglial tumors have been described in affected individuals. We present a 30-year follow-up on the family of a deceased patient who synchronously developed malignant neuroblastoma (NBL), PCC, and renal cell carcinoma (RCC). Other family members with late onset disease have come to our attention, and molecular study revealed a mutation in the SDHB gene. Despite the embryologic relationship, NBL has been seen in only two previous patients with familial PGL/PCC, both with deletions of the SDHB gene. Review of the literature suggests the lack of a reported association between NBL and familial PGL/PCC may be an ascertainment bias. We further suggest that study of the SDH genes in NBL survivors who develop secondary solid tumors, particularly RCC, may correct this bias, and provide for more effective and comprehensive tumor screening in this patient population. © 2010 Wiley-Liss, Inc.

Von Hippel–Lindau syndrome is a multisystem disorder inherited as an incompletely penetrant autosomal dominant trait. The chief features of the syndrome are tumors, both benign and malignant. Multiple visceral cysts are common as well. The von Hippel–Lindau gene, located on chromosome 3p25-26 is a recessive tumor-suppressor gene. Its function is complex. Some genotype-phenotype correlation exists. Effective treatment can be accomplished by early clinical and molecular identification of gene carriers. Anticipatory guidance is the key. Keywords: fibronectin assembly; hemangioblastoma; hypoxia-inducible factor; mRNA elongation; pheochromocytoma; polycythemia; chuvash type; renal cell carcinoma; tumor suppressor; Von Hippel-Lindau

Hunter-MacDonald syndrome (HMS) is a rare, autosomal dominant skeletal dysplasia with multiple malformations. The skeletal manifestations of HMS include short stature, scoliosis, epiphyseal dysplasia with early osteoarthritis leading to joint replacement, prominent humeral insertions for the deltoids, camptodactyly, subluxation of the thumbs, and malformed feet. Craniofacial manifestations include normal head circumference, tall forehead, bitemporal narrowing, ptosis, short palpebral fissures, and short philtrum. Decreased hearing acuity, transient cranial nerve palsies, congenital heart defects, and meningioma are also reported. Herein, we present two cases, and, through review of the manifestations of HMS in affected and at-risk family members, we have observed that predisposition to brain tumor is a cardinal feature of this condition.

Recently, we evaluated a 27-month-old boy with congenital generalized nonspecific myopathy, Mobius sequence, Robin sequence, and failure to thrive. We think the child has the same entity described by Carey, Fineman, and Ziter in 1982 [J Pediatr 101:353-364] and as such represents only the third example of this unusual syndrome. Review of the large number of conditions in which the Robin sequence occurs supports heterogeneity. Our case strengthens the Mobius-Robin association and further defines the Carey-Fineman-Ziter syndrome as a viable entity. It is most likely inherited as an autosomal recessive trait.

The Genetic Alliance represents more than 280 consumer and professional organizations and three million individuals, working together to enhance the lives of everyone affected by genetic conditions. As a central resource nexus, the Alliance provides an information hotline, technical assistance to support groups, public policy consultation and public and healthcare professional education. The Information Resource Center Helpline, staffed by a genetic counselor and full-time intern, has been at the core of the Alliance mission since 1986. Callers are linked to relevant, up-to-date information, referrals and resources about all things genetic through a number of different venues. Over the 12 month period (11/1/98 to 11/1/99), we answered 1435 phone calls, 619 emails, and 79 letters. During that same time, our website received 435,857 hits. The majority of callers (46%) seek information about specific genetic conditions (both common and rare). This is followed by individuals interested in support group referrals (19%) and Alliance information (11%). Most of the callers are either affected individuals (15%) or family members (38%). Others are health professionals (13%) and students (7%). Many of these individuals learn about the Alliance through our website (13%). This is especially true for those who use the e-mail Helpline to access information and resources. Other users contact the Helpline through referrals in published directories (12%) and the genetics/healthcare community (9%). When a call comes into the Helpline, the phone is answered promptly, concerns are validated, requests are assessed, and a comprehensive search is done for answers. Calls on the Helpline range in duration from less than one minute to over 20 minutes, with the average call taking about 6 minutes to complete. Helpline services center around referrals to established and credible consumer and professional resources, in particular support and research organizations and genetic specialists. We plan to expand collaborative efforts with the professional community to better serve the people who rely on our unique services.

We report on a family ascertained because of sibs affected with nasopharyngeal carcinoma. Other relatives had aplastic anemia or other malignancies and most were born of consanguineous parents. Epstein-Barr virus has been strongly implicated in the pathogenesis of nasopharyngeal carcinoma. It has also been suggested as a cause of aplastic anemia and other neoplasms. We postulate that this extensive German-Mennonite family has a heritable defect in the immune response to Epstein-Barr virus making its members at excessive risk for a number of different malignancies. This immunologic predisposition may be HLA associated and appears to be inherited as an autosomal recessive trait.

We describe monozygotic twins with thanatophoric dysplasia who were discordant for the Kleeblattschädel anomaly, but were identical in all other respects, including the histologic appearance of the endochondral growth plate. The observation suggests that the skull anomaly represents a variable manifestation of thanatophoric dysplasia, and that its occurrence in an infant with this bone dysplasia should not alter the low recurrence risk generally given.

Brachyolmia recessive type (Hobaek) is a rare bone dysplasia characterized by short trunk dwarfism that becomes evident during childhood. The radiographic manifestations are primarily limited to the spine, and consist of universal platyspondyly with lateral extension of the vertebral bodies beyond the pedicles and irregularity of the vertebral end plates. Histologic changes seen on growth plate biopsy permit the diagnosis to be confirmed. The inheritance pattern appears to be autosomal-recessive.

We report on 4 boys (3 in one family) who have a remarkably constant syndrome of childhood-onset choreoathetosis with later spasticity, postnatal microcephaly, growth and mental retardation, apparent external ophthalmoplegia and varying degrees of deafness. The pedigrees are consistent with X-linked inheritance. The syndrome is compared and contrasted with others comprising basal ganglion dysfunction in childhood. It is concluded that clinically and genetically the condition is unique.

We describe a family in which many persons have generalized joint laxity frequently complicated by dislocation of major joints. The condition is an autosomal dominant trait, with high penetrance. The disorder observed in this family and in others from the literature appears to be a specific syndrome that can be distinguished from other familial forms of joint laxity such as simple familial joint laxity and the Ehlers-Danlos syndromes. It has been designated the familial joint instability syndrome.

Renal cell carcinomas occurred in 6 of 17 subjects with the von Hippel-Lindau syndrome (HLS). In 4 patients, the tumors were discovered by abdominal computed tomography (CT) during a prospective study. Abdominal CT is recommended as a safe and accurate method for screening patients with HLS for renal cell carcinoma. Renal cell carcinoma in HLS tends to be multifocal and bilateral. Because of this, it is recommended that the tumors be treated by surgical enucleation rather than by more extensive surgical procedures which might ultimately lead to the need for dialysis.

A case of proximal 3p deletion is reported in tumor cells from a patient with renal cell carcinoma and von Hippel-Lindau disease. This is the first report of this deletion with renal cell carcinoma. With the previously detected translocations at the same breakpoint, this report confirms the 3p14 breakpoint as critical in this neoplasm. This strongly suggests that renal cell carcinoma results from a change in the genetic material in the proximal short arm of chromosome #3.