Novel In-Frame Deletion in HTRA1 Gene, Responsible for Stroke at a Young Age and Dementia—A Case Study

Biallelic mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene are known to cause an extremely rare cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which belongs to the group of hereditary cerebral small vessel diseases and is mainly observed in the Japanese population. Even though this pathology is inherited in an autosomal recessive manner, recent studies have described symptomatic carriers with heterozygous HTRA1 mutations who have milder symptoms than patients with biallelic HTRA1 mutations. We present the case of a Lithuanian male patient who had a stroke at the age of 36, experienced several transient ischemic attacks, and developed an early onset, progressing dementia. These clinical symptoms were associated with extensive leukoencephalopathy, lacunar infarcts, and microbleeds based on brain magnetic resonance imaging (MRI). A novel heterozygous in-frame HTRA1 gene deletion (NM_002775.5:c.533_535del; NP_002766.1:p.(Lys178del)) was identified by next generation sequencing. The variant was consistent with the patient’s phenotype, which could not be explained by alternative causes, appeared highly deleterious after in silico analysis, and was not reported in the medical literature or population databases to date.

Pharmacogenomic testing and prescribing patterns for patients with cancer in a large national precision medicine cohort

Population databases could help patients with cancer and providers better understand current pharmacogenomic prescribing and testing practices. This retrospective observational study analysed patients with cancer, drugs with pharmacogenomic evidence and related genetic testing in the National Institutes of Health All of Us database. Most patients with cancer (19 633 (88.3%) vs 2590 (11.7%)) received ≥1 drug and 36 (0.2%) received genetic testing, with a significant association between receiving ≥1 drug and age group (p<0.001), but not sex (p=0.612), race (p=0.232) or ethnicity (p=0.971). Drugs with pharmacogenomic evidence—but not genetic testing—were common for patients with cancer, reflecting key gaps preventing precision medicine from becoming standard of care.

Driving mosaicism: somatic variants in reference population databases and effect on variant interpretation in rare genetic disease

Background Genetic variation databases provide invaluable information on the presence and frequency of genetic variants in the ‘untargeted’ human population, aggregated with the primary goal to facilitate the interpretation of clinically important variants. The presence of somatic variants in such databases can affect variant assessment in undiagnosed rare disease (RD) patients. Previously, the impact of somatic mosaicism was only considered in relation to two Mendelian disease-associated genes. Here, we expand the analyses to identify additional mosaicism-prone genes in blood-derived reference population databases. Results To identify additional mosaicism-prone genes relevant to RDs, we focused on known/previously established ClinVar pathogenic and likely pathogenic single-nucleotide variants, residing in genes associated with early onset, severe autosomal dominant diseases. We asked whether any of these variants are present in a higher-than-expected frequency in the reference population databases and whether there is evidence of somatic origin (i.e., allelic imbalance) rather than germline heterozygosity (~ half of the reads supporting alternative allele). The mosaicism-prone genes identified were further categorized according to the processes they are involved in. Beyond the previously reported ASXL1 and DNMT3A, we identified 7 additional autosomal dominant RD-associated genes with known pathogenic single-nucleotide variants present in the reference population databases and good evidence of allelic imbalance: BRAF, CBL, FGFR3, IDH2, KRAS, PTPN11 and SETBP1. From this group of 9 genes, the majority (n = 7) was important for hematopoiesis. In addition, 4 of these genes were involved in cell proliferation. Further assessment of the known 156 hematopoietic genes led to identification of 48 genes (21 not yet associated with RDs) with at least some evidence of mosaicism detectable in reference population databases. Conclusions These results stress the importance of considering genes involved in hematopoiesis and cell proliferation when interpreting the presence and frequency of genetic variants in blood-derived reference population databases, both public and private. This is especially important when considering new variants of uncertain significance in known hematopoietic/cell proliferation RD genes and future novel gene–disease associations involving this class of genes.

Case Report: Novel Compound Heterozygous Variants in TRIOBP Associated With Congenital Deafness in a Chinese Family

Autosomal recessive non-syndromic deafness-28 (DFNB28) is characterized by prelingual, profound sensorineural hearing loss (HL). The disease is related to variants of the TRIOBP gene. TRIO and F-actin binding protein (TRIOBP) plays crucial roles in modulating the assembly of the actin cytoskeleton and are responsible for the proper structure and function of stereocilia in the inner ear. This study aimed to identify pathogenic variants in a patient with HL. Genomic DNA obtained from a 33-year-old woman with HL was evaluated using a disease-targeted gene panel. Using next generation sequencing and bioinformatics analysis, we identified two novel TRIOBP c.1170delC (p.S391Pfs*488) and c.3764C &gt; G (p.S1255*) variants. Both parents of the patient were heterozygous carriers of the gene. The two variants have not been reported in general population databases or published literature. The findings of this study will broaden the spectrum of pathogenic variants in the TRIOBP gene.

Biallelic Variants in KIF17 Associated with Microphthalmia and Coloboma Spectrum

Microphthalmia, anophthalmia, and coloboma (MAC) are a group of congenital eye anomalies that can affect one or both eyes. Patients can present one or a combination of these ocular abnormalities in the so called “MAC spectrum”. The KIF17 gene encodes the kinesin-like protein Kif17, a microtubule-based, ATP-dependent, motor protein that is pivotal for outer segment development and disc morphogenesis in different animal models, including mice and zebrafish. In this report, we describe a Sicilian family with two siblings affected with congenital coloboma, microphthalmia, and a mild delay of motor developmental milestones. Genomic DNA from the siblings and their unaffected parents was sequenced with a clinical exome that revealed compound heterozygous variants in the KIF17 gene (NM_020816.4: c.1255C > T (p.Arg419Trp); c.2554C > T (p.Arg852Cys)) segregating with the MAC spectrum phenotype of the two affected siblings. Variants were inherited from the healthy mother and father, are present at a very low-frequency in genomic population databases, and are predicted to be deleterious in silico. Our report indicates the potential co-segregation of these biallelic KIF17 variants with microphthalmia and coloboma, highlighting a potential conserved role of this gene in eye development across different species.

Excipients in the Paediatric Population: A Review

This theoretical study seeks to critically review the use of excipients in the paediatric population. This study is based on the rules and recommendations of European and American drug regulatory agencies. On the one hand, this review describes the most frequent excipients used in paediatric medicine formulations, identifying the compounds that scientific literature has marked as potentially harmful regarding the side effects generated after exposure. On the other hand, this review also highlights the importance of carrying out safety -checks on the excipients, which, in most cases, are linked to toxicity studies. An excipient in the compilation of paediatric population databases is expected to target safety and toxicity, as in the STEP database. Finally, a promising pharmaceutical form for child population, ODT (Orally Disintegrating Tablets), will be studied.

The effect of population distribution measures on evaluating spatial accessibility of primary health-care institutions: A case study from China

Improvement of the equality of geographical allocation of limited health-care resources requires an accurate evaluation of spatial accessibility of the facilities. The adoption of appropriate population distribution measures is one of the leading factors affecting such an evaluation. Using primary health-care institutions in Hainan, China as an example, this study aimed to explore the disparities embedded in spatial accessibility evaluations based on six common measures of population distribution, namely community/ village population (VillagePop), average population distribution (AveragePop), population distribution by night-time light intensity (NighttimelightPop) together with the public population databases LandScan, WorldPop and PoiPop for construction of the weights. The enhanced two-step floating catchment area method, two-way analysis of variance (ANOVA), Dunnett test, root mean square error and the mean absolute error were employed to assess and compare spatial accessibilities based on these different population distribution measures. The spatial accessibility of primary health-care institutions in Hainan was found to vary when plotted using the various population distribution measures mentioned. As indicated by the statistical outcomes of both ANOVA and the Dunnett test, using the spatial accessibility calculated by VillagePop as reference, those calculated by AveragePop and PoiPop were found to be significantly different. In addition, the spatial accessibilities calculated by AveragePop and PoiPop demonstrated higher error rates in the identification of underserved areas compared with the reference. Considering the limitations of public population databases, the adoption of night-time light data is highly recommended for estimating population distribution in the absence of high-resolution data.