Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype.

PURPOSE: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. METHODS: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. RESULTS: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. CONCLUSION: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.

Familial segregation of a 5q15-q21.2 deletion associated with facial dysmorphism and speech delay.

We report a two-generation family with four females harboring an 8.5Mb heterozygous deletion of 5q15-q21.2 who present with dysmorphic craniofacial features and speech delay. We hypothesize haploinsufficiency of CHD1 to be contributing to the clinical features observed in this family.

Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar.

Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as "likely pathogenic" (LP) or "pathogenic" (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.

Malignant Peripheral Nerve Sheath Tumor in a Patient With BAP1 Tumor Predisposition Syndrome.

BACKGROUND: Germline pathogenic variants in BRCA1-associated protein-1 (BAP1), a nuclear ubiquitin carboxy-terminal hydrolase with evidence suggestive of independent tumor suppressor function, predispose affected families to uveal melanoma, cutaneous melanoma, renal cell carcinoma, malignant mesothelioma, and possibly a range of other tumors and malignancies as part of the BAP1 tumor predisposition syndrome, a recently recognized hereditary cancer syndrome. CASE DESCRIPTION: A 50-year-old woman presented with a malignant peripheral nerve sheath tumor of the left fifth metatarsal head. Further examination revealed a right renal mass and left breast mass. Her family history was significant for astrocytoma, melanoma, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, prostate cancer, non-Hodgkin lymphoma, and pancreatic adenocarcinoma. Genetic testing revealed a BAP1 mutation in the proband. CONCLUSIONS: Although there have been reports of sarcomas and meningiomas in patients affected with BAP1 mutations, to our knowledge malignant peripheral nerve sheath tumors in this patient population have not been previously reported. We report a case of malignant peripheral nerve sheath tumor in a patient affected by a BAP1 mutation.

Pathologic findings in breast, fallopian tube, and ovary specimens in non-BRCA hereditary breast and/or ovarian cancer syndromes: a study of 18 patients with deleterious germline mutations in RAD51C, BARD1, BRIP1, PALB2, MUTYH, or CHEK2.

Germline BRCA mutations account for a significant proportion of genetic/familial risk of breast and ovarian cancer (GBOC) susceptibility, but a broader spectrum of GBOC susceptibility genes has emerged in recent years. Genotype-to-phenotype correlations are known for some established forms of GBOC; however, whether such correlations exist for less common GBOC variants is unclear. We reviewed our institution's experience with non-BRCA GBOC, looking specifically for trends in pathologic and clinical features. Eighteen women with deleterious germline mutations in RAD51C (5 patients), BARD1 (1 patient), BRIP1 (2 patients), PALB2 (3 patients), MUTYH (2 patients), or CHEK2 (5 patients) were identified between January 2011 and December 2016. Thirteen (72%) of 18 patients developed carcinoma of the breast, fallopian tube, or ovary, with 1 patient developing 2 separate primary neoplasms. Twelve (86%) of 14 tumors occurred in the breast. One (7%) arose in the fallopian tube and another (7%) arose in the ovary. Evidence of genotype-phenotype correlation was not identified. However, some data suggest that the type of alteration in select genes may influence tumor behavior and patient outcome. In our PALB2 mutation cohort, 2 patients with frameshift mutations led to early onset and rapid progression to stage IV breast cancer in contrast to stage IA breast cancer in 1 patient with a nonsense mutation. Despite no apparent genotype-phenotype trends, our data indicate that some loss-of-function variants in PALB2 may lead to differences in tumor behavior and patient outcome.

Further Defining the Role of the Laboratory Genetic Counselor.

Laboratory genetic counseling is becoming increasingly common as a result of increased laboratory services and genetic testing menus, as well as growing job responsibilities. Christian et al. (2012) provided the first quantitative data regarding the roles of the laboratory-based genetic counselor (LBGC) finding that two of the most prevalent roles are as customer liaisons and communicators of test results. The goal of the present study was to further delineate the role of the LBGC by addressing specific tasks that LBGCs are involved with on a day-to-day basis. A survey was designed to expand upon themes identified in the Christian et al. (2012) study by querying specific tasks performed in several categories of potential LBGC job duties. An invitation for LBGCs to participate was distributed via email to the membership of the National Society of Genetic Counselors (NSGC) and the Canadian Association of Genetic Counsellors (CAGC). We identified 121 genetic counselors who primarily work in the laboratory setting or whose job role includes a laboratory component. Almost all respondents performed customer liaison/case coordination (95 %), and interpretation and result reporting (88 %). The most frequently performed tasks within these categories involved addressing questions from clients, making phone calls with genetic testing results, obtaining clinical or family history information for results interpretation, and composing case-specific interpretations for unique results and/or obtaining literature references to support interpretations. The study results also point to trends of expanding roles in sales and marketing, variant interpretation and management responsibilities. Results of this study may be useful to further define the full scope of practice of LBGCs, aid in the development of new LBGC positions and expand current positions to include roles related to test development, research, and student supervision. It may also aid in curriculum updates for training programs to increase exposure to LBGC roles.

PMS2 monoallelic mutation carriers: the known unknown.

Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.Genet Med 18 1, 13-19.

The utilization of counseling skills by the laboratory genetic counselor.

The number of available genetic testing options and the nuances associated with these options continue to expand. In addition, the scope of genetic testing has broadened to areas and specialties beyond Medical Genetics. In response to these changes, diagnostic laboratories have employed genetic counselors to help navigate the increasing complexity of genetic testing, given their expertise and training in human genetics. However a largely unrecognized aspect of this role involves the use of counseling skills. Counseling skills are used by laboratory genetic counselors in a variety of situations to convey information and facilitate understanding among clinicians and medical staff. This helps to reduce test ordering errors, promote optimal test utilization, and ensure best patient care practices. The specific counseling skills used by laboratory counselors will be explored using three fictional case vignettes, followed by a discussion of the applicability of these skills in other contexts. Exploration of the unique ways in which laboratory genetic counselors apply their counseling skills can be useful for professional development and instructive for graduate training programs.

Genetic testing utilization and the role of the laboratory genetic counselor.

Laboratory genetic counselors within hospital laboratories and genetic testing laboratories have an important role in increasing the appropriate utilization of genetic tests. This service is becoming more important as genetic testing becomes more complex and the demand for genetic testing in healthcare increases. Additionally genetic tests are among the most expensive assays in the clinical laboratory test catalog. Laboratory genetic counselors are able to increase genetic test utilization through review and assessment of the appropriateness of the ordered testing, developing protocols, and by increasing communication with ordering providers.

Genetics of adult glioma.

Gliomas make up approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Despite the frequency of gliomas, the etiology of these tumors remains largely unknown. Diffuse gliomas, including astrocytomas and oligodendrogliomas, belong to a single pathologic class but have very different histologies and molecular etiologies. Recent genomic studies have identified separate molecular subtypes within the glioma classification that appear to correlate with biological etiology, prognosis, and response to therapy. The discovery of these subtypes suggests that molecular genetic tests are and will be useful, beyond classical histology, for the clinical classification of gliomas. While a familial susceptibility to glioma has been identified, only a small percentage of gliomas are thought to be due to single-gene hereditary cancer syndromes. Through the use of linkage studies and genome-wide association studies, multiple germline variants have been identified that are beginning to define the genetic susceptibility to glioma.