Proximal variants in CCND2 associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes.

Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2-CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. Megalencephaly-associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation-resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop-gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes.

PillHarmonics: An Orchestrated Pharmacogenetics Medication Clinical Decision Support Service.

OBJECTIVES: Pharmacogenetics (PGx) is increasingly important in individualizing therapeutic management plans, but is often implemented apart from other types of medication clinical decision support (CDS). The lack of integration of PGx into existing CDS may result in incomplete interaction information, which may pose patient safety concerns. We sought to develop a cloud-based orchestrated medication CDS service that integrates PGx with a broad set of drug screening alerts and evaluate it through a clinician utility study. METHODS: We developed the PillHarmonics service for implementation per the CDS Hooks protocol, algorithmically integrating a wide range of drug interaction knowledge using cloud-based screening services from First Databank (drug-drug/allergy/condition), PharmGKB (drug-gene), and locally curated content (drug-renal/hepatic/race). We performed a user study, presenting 13 clinicians and pharmacists with a prototype of the system's usage in synthetic patient scenarios. We collected feedback via a standard questionnaire and structured interview. RESULTS: Clinician assessment of PillHarmonics via the Technology Acceptance Model questionnaire shows significant evidence of perceived utility. Thematic analysis of structured interviews revealed that aggregated knowledge, concise actionable summaries, and information accessibility were highly valued, and that clinicians would use the service in their practice. CONCLUSION: Medication safety and optimizing efficacy of therapy regimens remain significant issues. A comprehensive medication CDS system that leverages patient clinical and genomic data to perform a wide range of interaction checking and presents a concise and holistic view of medication knowledge back to the clinician is feasible and perceived as highly valuable for more informed decision-making. Such a system can potentially address many of the challenges identified with current medication-related CDS.

Ordering and Interpreting Precision Oncology Studies for Adults With Advanced Solid Tumors: A Primer.

Background: The promise of precision oncology can only be realized when genetic alterations are identified that can be leveraged to improve response and minimize toxicity. Identifying those alterations requires the knowledge to order the right test and to interpret the results correctly. This primer is designed to help clinicians order the appropriate testing for patients with specific malignancies and to give them an informed approach to interpretation. Observations: Germline DNA is usually acquired from peripheral blood, buccal swab, or saliva collection in patients with a metastatic malignancy and can provide treatment options otherwise not available. However, germline testing does not indicate alterations that arise solely in tumor tissue. Somatic testing may be performed on primary tumor, metastatic biopsy, or circulating tumor DNA when the alteration is present at the time that the tumor developed and expected to be carried through the evolution of the tumor. Conclusions: The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for individuals dealing with malignancy as does our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.

A Case of Magnusiomyces capitatus Peritonitis Without Underlying Malignancies.

Magnusiomyces capitatus is a rare cause of fungal infection in immunocompromised patients, mainly seen in hematological malignancies. M capitatus infections are extremely rare in immunocompetent patients, as it is part of normal human microbial flora. We are presenting an extremely rare case of M capitatus peritonitis in an otherwise immunocompetent patient who suffered from gastrointestinal leakage due to pancreatitis. Fungal identification was performed at reference laboratory by phenotypic characteristics and DNA sequencing of target internal transcribed spacer region of the rRNA gene and the D1-D2 domain of the large-subunit rRNA gene and susceptibility testing by Clinical and Laboratory Standards Institute guidelines (document M27-S4) broth dilution method. He was successfully treated with a combination of surgical repair and voriconazole single therapy.