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Purpose Whole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants. Methods We present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets. Results Using the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001). Conclusion We outline a statistically robust framework for assessing whether a variant is “too common” to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.

Pediatric cataracts are a significant cause of vision loss in children and may present in isolation or in association with other ocular or systemic diseases. Despite advances in molecular diagnostics, the underlying etiology of cataracts in most patients remains unknown, even in the setting of a positive family history. Genetic testing for pediatric cataracts is neither standardized nor widely utilized. Lack of standardization is multifold, including limited published clinical and experimental reports and the absence of a comprehensive list of candidate genes with grading of the strength of gene-disease relationships. The purpose of this review is to provide a comprehensive list of the 81 candidate genes potentially associated with non-syndromic pediatric cataracts and the accompanying case-based and experimental literature support in order to start the process of developing a standardized approach to genetic testing. Inheritance patterns, other associated ocular findings, and proposed mechanisms of pathogenesis will be described for the candidate genes. Genes that are associated with two distinct phenotypes, one syndromic and one characterized by non-syndromic cataracts, will also be presented. The types of cataracts and age of onset are often highly variable at both the gene and variant level, so they will not be the focus of this review, but are of interest for future studies. Future work is needed to formalize a standardized list of established and candidate genes for non-syndromic pediatric cataracts and to systematically grade our confidence in the gene-disease relationships through the ClinGen framework. An improvement in genetic testing for pediatric cataracts will improve clinical care of these patients and their families regarding prognostication, personalized medical management, and clarification of recurrence risk for reproductive decision making. Further, a better understanding of the pathogenesis of pediatric cataracts can lead to targets for novel treatment development.

Background Homozygous or compound heterozygous pathogenic variants in the thromboxane A synthase 1 (TBXAS1) gene are associated with Ghosal hematodiaphyseal dysplasia (GHDD) which is characterized by defective hematopoiesis and increased bone density of long bones. Methods Patients 1 and 2 are identical twins, who presented with red blood cell transfusion‐dependent normocytic anemia and thrombocytopenia with bone marrow fibrosis and cortical bone thickening of long bones on plain radiograph. To clarify the etiology of their anemia and thrombocytopenia, whole blood was used for the DNA extraction and analyzed using next‐generation sequencing (NGS) on an in‐house bone marrow failure syndrome panel. Results The NGS results indicated that these two patients carried two heterozygous variants in TBXAS1, exon7, c.583_584del, p.Ala195Leufs*12, and exon12, c.1420G>T, p.Gly474Trp, which were inherited from their mother and father, respectively. Patients 1 and 2 have been on chronic oral steroids with normalization of hemoglobin and platelet count after steroid initiation. Patient 3 is their sister who has normal blood counts but also has the same variants in TBXAS1 as her brothers. Radiographs showed cortical bone thickening and she has not required any treatment or transfusion. Conclusion We report three Caucasian siblings from non‐consanguineous parents with novel compound heterozygous variants of TBXAS1 presenting with the phenotypes of GHDD. These three cases illustrate the variable clinical expressivity of the GHDD from two‐compound heterozygous pathogenic variants of TBXAS1. We report three Caucasiion siblings from non‐consanguineous parents with novel compound heterozygous variants of TBXAS1 presenting with phenotypes of GHDD. Patient 1 and 2 are identical twins, who presented with red blood cell transfusion dependent normocytic anemia and thrombocytopenia with bone marrow fibrosis and cortical bone thickening of long bones on plain radiograph. Patient 3 is their sister with normal blood counts but cortical bone thickening on radiograph who has not required any treatment. These three cases illustrate the variable clinical expressivity of the GHDD from two‐compound heterozygous pathogenic variants of TBXAS1.

The aim of this study was to evaluate the diagnostic yield from prior genetic testing in a 20-year cohort of pediatric patients with congenital cataracts. A retrospective review of patients with congenital cataracts who underwent genetic testing was completed from 2003–2022. The diagnostic yield of the test was determined by variant classification and inheritance pattern. Variants from initial testing underwent reclassification in accordance with ACMG-AMP (American College of Medical Genetics and Genomics—American Association of Molecular Pathology) 2015 or 2020 ACMG CNV guidelines. A total of 95 variants were identified in 52 patients with congenital cataracts (42 bilateral, 10 unilateral); 42 % were White, 37% were Hispanic, 8% were Black, and 6% were Asian. The majority of patients (92%) did not have a family history of congenital cataracts but did have systemic illnesses (77%). Whole exome sequencing and targeted congenital cataract panels showed diagnostic yields of 46.2% and 37.5%, respectively. Microarray had the lowest yield at 11%. Compared to the initial classification, 16% (15 of 92 variants) had discrepant reclassifications. More testing is needed, and an increased focus is warranted in the field of ocular genetics on congenital cataracts, particularly in those with systemic illnesses and no family history, to advance our knowledge of this potentially blinding condition.

MAF encodes a transcription factor involved in T-helper-2 (Th2) cell differentiation. Heterozygous pathogenic variants in MAF have been observed in both isolated and syndromic congenital cataract cases; genotype–phenotype correlations are based on the location of the variant within the gene. Variants in the N-terminus domain of MAF are associated with cataracts as part of Aymé-Gripp syndrome. The purpose of this report is to expand the ocular phenotypic spectrum of Aymé-Gripp syndrome by describing a patient with MAF variant c.185C>G, p.Thr62Arg, and the traditional systemic findings and congenital cataracts as well as an unusual feature of pigmentary retinopathy, which has not been previously reported in Aymé-Gripp syndrome. Additionally, a comprehensive review of the literature was completed to report ocular genotype–phenotype data on previously reported patients with MAF-associated Aymé-Gripp syndrome.

The diagnostic yield of genetic testing for ocular/oculocutaneous albinism (OA/OCA) in a diverse pediatric population in the United States (U.S.) is unclear. Phenotypes of 53 patients who presented between 2006–2022 with OA/OCA were retrospectively correlated with genetic testing results. Genetic diagnostic yield was defined as detection of pathogenic/likely pathogenic variant(s) matching the anticipated inheritance for that gene–disease relationship. Variant reclassifications of those with variants of uncertain significance (VUS) and without positive diagnostic yield were completed. Overall initial genetic diagnostic yield of OA/OCA was 66%. There was no significant difference (p = 0.59) between race and ethnicities (Black (78%), White (59%), Hispanic/Latino (64%)); however, the diagnostic yield of OA (33%) was significantly lower (p = 0.007) than OCA (76%). Causative variants in OCA2 (28%) and TYR (20%) were most common. Further, Hermansky–Pudlak syndrome variants were identified in 9% of patients. Re-classification of VUS in non-diagnostic cases resulted in genetic diagnoses for 29% of individuals and increased overall diagnostic yield to 70% of all subjects. There is a high diagnostic yield of genetic testing of patients overall with OA/OCA in a diverse U.S. based pediatric population. Presence or absence of cutaneous involvement of albinism significantly affects genetic diagnostic yield.

Two dimensional (2D) full-field digital mammography is the current standard of breast cancer screening. Digital breast tomosynthesis generates pseudo-three dimensional datasets of the breast from which synthesised 2D (s2D) mammograms can be reconstructed. This innovative approach reduces the likelihood of overlapping breast tissues that can conceal features of malignancy. We aimed to compare digital breast tomosynthesis plus s2D mammography with digital screening mammography for the detection of invasive breast cancer. TOSYMA was a randomised, open-label, superiority trial done at 17 screening units in two federal states of Germany. Eligible participants were women aged 50–69 years who had been invited to participate in a population-wide, quality-controlled mammography screening programme. Women were randomly assigned (1:1) to digital breast tomosynthesis plus s2D mammography or digital mammography alone using block randomisation (block size of 32), stratified by site. The primary endpoints were the detection rate of invasive breast cancer and invasive interval cancer rate at 24 months, analysed in the modified full analysis set, which included all randomly assigned participants who underwent either type of screening examination. Ten examinations, corresponding to a second study participation, were excluded. Analyses were done according to the intention-to-treat principle. Interval cancer rates will be reported in the follow-up study. Safety was assessed in the as-treated population, which included all participants who were randomly assigned. This trial is registered with ClinicalTrials.gov, NCT03377036, and is closed to accrual. Between July 5, 2018, and Dec 30, 2020, 99 689 women were randomly assigned to digital breast tomosynthesis plus s2D mammography (n=49 804) or digital mammography (n=49 830). Invasive breast cancers were detected in 354 of 49 715 women with evaluable primary endpoint data in the digital breast tomosynthesis plus s2D group (detection rate 7·1 cases per 1000 women screened) and in 240 of 49 762 women in the digital mammography group (4·8 cases per 1000 women screened; odds ratio 1·48 [95% CI 1·25–1·75]; p<0·0001). Adverse events and device deficiencies were rare (six adverse events in each group; 23 device deficiencies in the digital breast tomosynthesis plus s2D group vs five device deficiencies in the digital mammography group) and no serious adverse events were reported. The results from this study indicate that the detection rate for invasive breast cancer was significantly higher with digital breast tomosynthesis plus s2D mammography than digital mammography alone. Evaluation of interval cancer rates in the follow-up study will further help to investigate incremental long-term benefits of digital breast tomosynthesis screening. Deutsche Forschungsgemeinschaft (German Research Foundation).

Background/Objectives: While ocular albinism (OA) is usually associated with reduced vision, nystagmus, and foveal hypoplasia, there is phenotypic variability in iris and fundus hypopigmentation. Hemizygous pathogenic/likely pathogenic (P/LP) variants in GPR143 at X: 151.56–151.59 have been shown in the literature to be associated with OA. The purpose of this study was to report the case of a Hispanic male with X-linked inherited OA associated with a hemizygous GPR143 variant and to review the literature relating to genotype–phenotype associations with GPR143 and OA. Methods: After consent to an IRB-approved protocol, a 14-year-old Hispanic male patient with OA and his parents underwent whole genome sequencing (WGS) in 2023. Two maternal uncles with nystagmus underwent targeted variant testing in 2024. A literature review of reported GPR143 variants was completed. Results: A male with reduced visual acuity, infantile-onset nystagmus, foveal hypoplasia, and iris hypopigmentation was identified to have the variant GPR143, c.455+3A>G, which was also present in his mother and two affected maternal uncles. This variant has been previously identified in other Hispanic patients of Mexican descent. Additionally, 127 variants were identified in the literature and reported to be associated with OA. All patients had reduced visual acuity (average 0.71 ± 0.23 logMAR), 99% had nystagmus, 97% foveal hypoplasia, 79% fundus hypopigmentation, and 71% iris hypopigmentation. Of those patients with reported optotype best corrected visual acuity (BCVA), eight (9%) had VA from 20/25 to 20/40, 24 (24%) had VA from 20/50 to 20/80, and 63 (67%) had VA from 20/100 to 20/200. The most frequent type of variant was missense (31%, n = 39). Frameshift and nonsense variants were associated with the lowest rates of iris hypopigmentation (50% [n = 11] and 44% [n = 8], respectively; p = 0.0068). Conclusions: This case represents phenotypic variability of GPR143-associated OA and highlights the importance of repeat genetic testing and independent analyses of test results for accurate variant classification, particularly in non-White and Hispanic patients. Further studies in more diverse populations are needed to better develop genotype–phenotype associations for GPR143-associated OA.

The MAF gene encodes a transcription factor in which pathogenic variants have been associated with both isolated and syndromic congenital cataracts. We aim to review the MAF variants in the C-terminal DNA-binding domain associated with non-syndromic congenital cataracts and describe a patient with a novel, disease-causing de novo missense variant. Published reports of C-terminal MAF variants and their associated congenital cataracts and ophthalmic findings were reviewed. The patient we present and his biological parents had genetic testing via a targeted gene panel followed by trio-based whole exome sequencing. A 4-year-old patient with a history of bilateral nuclear and cortical cataracts was found to have a novel, likely pathogenic de novo variant in MAF, NM_005360.5:c.922A>G (p.Lys308Glu). No syndromic findings or anterior segment abnormalities were identified. We report the novel missense variant, c.922A>G (p.Lys308Glu), in the C-terminal DNA-binding domain of MAF classified as likely pathogenic and associated with non-syndromic bilateral congenital cataracts.

IntroductionDilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 DCM patients across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60,706 individuals in order to identify clinically interpretable genes robustly associated with dominant monogenic DCM.MethodsWe used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 DCM patients and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 DCM patients sequenced in diagnostic laboratories and the ExAC database for replication and meta-analysis.ResultsSpecific variant classes in TTN, DSP, MYH7 and LMNA were associated with DCM in all comparisons. Variants in BAG3, TNNT2, TPM1, NEXN and VCL were significantly enriched specific patient subsets, with the last 3 genes likely contributing primarily to early-onset forms of DCM. Overall, rare variants in these 9 genes potentially explained 19–26% of cases. Whilst the absence of a significant excess in other genes cannot preclude a role in disease, such genes have limited diagnostic value since novel variants will be uninterpretable and therefore non-actionable, and their diagnostic yield is minimal.ConclusionIn the largest sequenced DCM cohort yet described, we observe robust disease association with 9 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes evaluated have limited value in diagnostic testing in DCM. This data will contribute to community gene curation efforts, and will reduce erroneous and inconclusive findings in diagnostic testing.Conflict of InterestNone