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Joubert syndrome (JS), a well-established ciliopathy, is characterized by the distinctive molar tooth sign on brain MRI, ataxia, and neurodevelopmental features. Other manifestations can include polydactyly, accessory frenula, renal, or liver disease. Here, we report individuals meeting criteria for JS with de novo heterozygous variants in SLC30A7 (Chr1p21.2). The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. Exome sequencing detected a de novo heterozygous missense variant in SLC30A7: NM_133496.5: c.407 T C, (p.Val136Ala). The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. A de novo deletion-insertion variant in SLC30A7, c.490_491delinsAG (p.His164Ser) was found. Both de novo variants affect highly conserved residues. Variants were not identified in known Joubert genes for either case. SLC30A7 has not yet been associated with a human phenotype. The SLC30 family of zinc transporters, like SLC30A7, permit cellular efflux of zinc, and although it is expressed in the brain its functions remain unknown. Published data from proteomic studies support SLC30A7 interaction with TCTN3, another protein associated with JS. The potential involvement of such genes in primary cilia suggest a role in Sonic Hedgehog signaling. SLC30A7 is a candidate JS-associated gene. Future work could be directed toward further characterization of SLC30A7 variants and understanding its function.

Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications in children, including pain and pathologic fractures. Mutations in cellular growth pathways are common, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, who were found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggesting additional targeted therapies could be effective.

Nicotinamide adenine dinucleotide (NAD) is an essential cofactor involved in over 400 cellular reactions. During embryogenesis, mammals synthesize NAD de novo from dietary L-tryptophan via the kynurenine pathway. Biallelic, inactivating variants in three genes encoding enzymes of this biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder. Here we have identified a further three families with biallelic variants in HAAO and four families with biallelic variants in KYNU. These patients present similarly with multiple malformations of the heart, kidney, vertebrae, and limbs, of variable severity. We show that each variant identified in these patients results in loss-of-function, revealed by significant reduction in NAD levels via yeast genetic complementation assays. For the first time missense mutations are identified as a cause of malformation and shown to disrupt enzyme function. These missense and frameshift variants cause moderate to severe NAD deficiency in yeast, analogous to insufficient synthesized NAD in patients. We hereby expand the genotypic and corresponding phenotypic spectrum of Congenital NAD Deficiency Disorder.

Lung cancer is the leading cause of cancer mortality. It is classified into different histologic subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma (commonly referred as non-small cell lung cancer) and small cell lung cancer. Comprehensive molecular characterization of lung cancer has expanded our understanding of the cellular origins and molecular pathways affected in each of these subtypes. Many of these genetic alterations represent potential therapeutic targets for which drugs are constantly under development. This article discusses the molecular characteristics of the main lung cancer subtypes and discusses the current guidelines and novel targeted therapies, including checkpoint immunotherapy.

Objectives: Although hereditary risk assessment is advised for all ovarian/tubal/peritoneal (OTP) cancer patients, a variety of barriers limit universal compliance. A workflow using tumor-based next generation sequencing (NGS) germline testing implemented by the pathologist at the time of primary or interval debulking surgery. The objective of this study is to report compliance and turnaround time of a pilot workflow of germline testing via tumor-based NGS in OTP cancer. may reduce some of these barriers. Methods: We identified all patients with a new diagnosis of epithelial OTP carcinoma who underwent primary or interval debulking surgery from January to August 2020. All patients were recommended to undergo tumor and germline sequencing, either through our institutional NGS platform or through commercial sequencing. We compared time to results as well as influence of results on maintenance/second-line therapy. Results: We identified 35 patients with a median age of 61 (range 29-78) and a median follow-up time of 5 months (range 0-13). Our stage breakdown included 8 Stage I, 4 Stage II, 20 Stage III, and 3 Stage IV patients. A total of 24 patients had high grade serous carcinoma, with 5 endometrioid, 3 clear cell, 2 mucinous, and one high grade NOS tumor. A total of 11 patients underwent interval debulking surgery after neoadjuvant chemotherapy. All but 2 (94.2%) of patients received a genetic counseling referral. A total of 2 patients did not have sequencing performed, while 1 patient did not have enough tumor for sequencing at the time of interval debulking surgery. A total of 10 patients had both tumor and germline sequencing performed at the time of tumor testing, while 20 others had tumor only sequencing. For those patients who did not have a known hereditary germline mutation prior to surgery, the mean turnaround time for germline genetic testing results was 26.5 days (range 19-51) in the NGS + germline group whereas the median turnaround time after commercial testing was 75 days (regardless of primary or interval debulking, range 19-202), p=0.006. A total of 5 patients were identified as germline carriers of the BRCA1 or BRCA2 mutation, with 1 addition germline finding of a pathogenic variant in ATM. An additional 5 patients had somatic pathogenic mutations in homologous recombination repair pathway genes, all of whom are receiving or being considered for PARP inhibitor maintenance after primary treatment. Conclusions: Combining somatic and germline tumor testing at the time of staging/debulking surgery requires upfront coordination with pathology and patient consent, but streamlines the genetic testing process to improve testing rates allow timely results for treatment planning. This approach may also identify additional patients with homologous recombination deficient tumors through simultaneous somatic mutation assessment.