Aims Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing’s syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical ...characteristics and pathogenic variants of PPNAD. Methods Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles. Results A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations ( PRKAR1A , PDE11A , PRKACA , CTNNB1 , PDE8B , and ARMC5 ) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD ( p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period. Conclusions For young patients with Cushing’s syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC. Systematic review registration https://www.crd.york.ac.uk/prospero , identifier CRD42023416988.
•The variants of ABCA4, ELOVL4, and PROM1 were found in Chinese patients with STGD.•One de novo variant, ABCA4 c.4253+4C>T, was identified in a Chinese family.•Eight novel variants in ABCA4 and ...ELOVL4 were confirmed in STGD patients.•Potential pathogenicity existed in these novel variants.
Stargardt disease (STGD) is the most frequent cause of hereditary macular dystrophy in childhood. Variants in the ABCA4, ELOVL4, PROM1, BEST1, and PRPH2 genes have been detected in patients with autosomal recessive or dominant STGD. This study was aimed at identifying the novel disease-associated variants in Chinese patients with STGD.
Ten Chinese families and two sporadic cases with STGD (n = 32) were enrolled in the study. All subjects underwent genetic analysis with next-generation sequencing (NGS), which was based on a specially customized capture panel targeting exons and untranslated regions (UTRs) of 792 genes related to common hereditary ophthalmopathy. Variants were analyzed to assess possible pathogenicity.
Fourteen disease-associated variants of ABCA4 were detected in 9 Chinese families with autosomal recessive STGD, including 11 pathogenic variants and 3 likely pathogenic variants. Variant c.4253 + 4C > T in ABCA4 was identified as one de novo variant. Of the 14 distinct variants in ABCA4, 7 novel variants were found. In addition, one known variant of PROM1, c.1117C > T (p.Arg373Cys), was detected in one family and one sporadic case with autosomal dominant STGD, respectively. One novel missense variant of ELOVL4, c.59A > G (p.Asn20Ser), was found in one sporadic case with autosomal dominant STGD. The potential deleterious effects of these novel variants were confirmed through intensive analysis.
By panel-based NGS, 8 novel disease-associated variants are identified in two genes responsible for STGD, including ABCA4 and ELOVL4. Our results further extend the mutation spectrum of these two genes in Chinese patients with STGD. One ABCA4 c.4253 + 4C > T variant is identified as a de novo splicing variant.
Pathogenic variation in HCN1 is now an established cause of epilepsy and intellectual disability. Variation in HCN1 causes a spectrum of disease with a genotype-phenotype relationship emerging. De ...novo pathogenic variants that occur in the transmembrane domains of the channel typically cause a cation 'leak' that associates with severe developmental and epileptic encephalopathy (DEE). Genotype-phenotype associations for variants that fall outside of the transmembrane domains are less well established but do include milder forms of epilepsy that can be either de novo or inherited. HCN1 DEE mouse models have been generated which recapitulate the seizures and learning difficulties seen in human patients. These mice have also acted as powerful preclinical models which share pharmacoresponsiveness with human HCN1 DEE patients. Data from these mouse models support the conclusion that anti-seizure medications with sodium channel block as their primary mechanism of action should be used with caution in HCN1 DEE. Other comorbidities of HCN1 DEE including retinal dysfunction have also been modelled in HCN1 DEE mice, suggesting HCN1 variants can cause a dramatically reduced sensitivity to light with limited ability to process temporal information. Our understanding of the genetics and pathophysiological mechanisms underlying HCN1 epilepsy has progressed significantly and is already influencing therapy. However, more research effort is needed to fully understand the natural histories of HCN1 epilepsies and to develop precision therapeutic approaches.
Cytochrome oxidase subunit II is encoded by the MT-CO2 gene and belongs to a large internal membrane complex called cytochrome c oxidase. To date, no pathogenic single nucleotide variant has been ...confirmed in this gene according to the MITOMAP database. The goal of this study was to review the literature and attempt to interpret all defined variants of the MT-CO2 gene, either directly associated with symptoms or only by the occurrence of variant in specific diseases.
Available databases were searched for clinically relevant variants in the MT-CO2 gene. Variant interpretation was based on HelixMTdb frequency, identification of conserved sites in primates, particularly Pan paniscus and Pan troglodytes sequences from GenBank, MITOMAP data and the status of the Predict program.
We found 23 single nucleotide variants in 30 papers where the authors suspected or directly linked variants with a specific phenotype. The most common method sequencing method was Sanger sequencing in 17 papers, and the next-generation sequencing in 6 papers.
Only two potentially pathogenic variants m.8163A > G and m.7887G > A were found, meeting almost all the restrictive criteria for confirmed mitochondrial pathogenic variants. Unfortunately, none of the variants described in all of the papers/databases analysed can be unquestionably classified as pathogenic. Considering that this is a critical respiratory chain subunit gene, further research is needed.
•Two children with antenatal BS showed different manifestations.•Exome sequencing identified three novel SLC12A1 mutations.•Four additional novel pathogenic/likely pathogenic variants of SLC12A1 and ...six in the SLC34A2 gene were identified.•Two children from one family who were affected by different rare conditions.
Bartter syndrome is an inherited renal tubular disorder that is characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. Bartter syndrome type 1 is caused by SLC12A1 mutations.
The patients were from two unrelated non-consanguineous Chinese families. Both patients presented with intrauterine growth retardation, premature delivery, failure to thrive, polyuria and metabolic alkalosis. Whole-exome sequencing was used to identify the causative gene.
Exome sequencing identified three novel SLC12A1 mutations in our patients. And we found the two patients had significantly different outcomes when they were two years of age. Moreover, we identified four novel variants of SLC12A1 that were likely to be pathogenic, from our in-house database. A review of the whole-exome sequencing data of patient 1 lead to her brother being genetically diagnosed with pulmonary alveolar microlithiasis, which was caused by compound heterozygous SLC34A2 variations.
We reported two children from one family who were affected by different rare conditions. This study expanded the mutation spectra of the SLC12A1 and SLC34A2 genes. We showed the important role of early genetic testing for disease diagnosis and emphasized the importance of standardized treatment and management.
Patients with breast cancer (BC) harbouring a germinal BRCA pathogenic variant (gBRCA-PV) may have an enhanced sensitivity to platinum-based chemotherapy (PBC) and PARP inhibitors (PARPi). As ...reported in ovarian cancer, however, sensitivity and resistance to these treatments could partially overlap. In patients with a gBRCA-PV and advanced BC (aBC), it remains unclear whether prior exposure to PARPi/PBC affects tumour response to subsequent PBC/PARPi, respectively.
We conducted a retrospective, multicentric study to investigate the clinical benefit of post-PBC PARPi and vice versa in patients with a gBRCA-PV and aBC. Patients included had received (neo)adjuvant PBC and then PARPi in advanced setting (group 1), PBC followed by PARPi (group 2) or PARPi followed by PBC (group 3), both in advanced setting. We reported median progression-free survival (mPFS) and disease control rate (DCR) in each group.
A total of 67 patients from six centres were included. PARPi-mPFS in advanced setting was 6.1 months in patients in group 1 (N = 12), while PARPi-DCR was 67%. In group 2 (N = 36), PARPi-mPFS was 3.4 months and PARPi-DCR was 64%. Age < 65 years and platinum-free interval (PFI) > 6 months were associated with longer PARPi-PFS; previous PBC-PFS > 6 months and PBC in first to second line were associated with longer PARPi-DCR. Patients in group 3 (N = 21) reported a PBC-mPFS of 1.8 months and a PBC-DCR of 14%. PARPi-PFS ≥ 9 months and PARPi-FI ≥ 6 months were associated with better PBC-DCR.
Sensitivity and resistance to PARPi and PBC partially overlap in patients with a gBRCA-PV and aBC. Evidence of PARPi activity emerged in patients who progressed on previous PBC.
•Sensitivity to PARPi and PBC partially overlaps in patients with a gBRCA-PV and aBC.•Evidence of PARPi activity emerged in platinum-resistant or -unresponsive aBC.•PBC/PARPi-free interval and PBC/PARPi-PFS impact on subsequent PARPi/PBC benefit.
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•The DeepSAV predictor of SAV functional impact was updated and improved.•The diversity of multiple sequence alignment is an important factor in DeepSAV performance.•DBSAV provides ...DeepSAV scores for human SAVs and GTS scores for human genes.•DBSAV is a valuable resource for mechanistic interpretation of human SAVs.
Deleterious single amino acid variation (SAV) is one of the leading causes of human diseases. Evaluating the functional impact of SAVs is crucial for diagnosis of genetic disorders. We previously developed a deep convolutional neural network predictor, DeepSAV, to evaluate the deleterious effects of SAVs on protein function based on various sequence, structural, and functional properties. DeepSAV scores of rare SAVs observed in the human population are aggregated into a gene-level score called GTS (Gene Tolerance of rare SAVs) that reflects a gene's tolerance to deleterious missense mutations and serves as a useful tool to study gene-disease associations. In this study, we aim to enhance the performance of DeepSAV by using expanded datasets of pathogenic and benign variants, more features, and neural network optimization. We found that multiple sequence alignments built from vertebrate-level orthologs yield better prediction results compared to those built from mammalian-level orthologs. For multiple sequence alignments built from BLAST searches, optimal performance was achieved with a sequence identify cutoff of 50% to remove distant homologs. The new version of DeepSAV exhibits the best performance among standalone predictors of deleterious effects of SAVs. We developed the DBSAV database (http://prodata.swmed.edu/DBSAV) that reports GTS scores of human genes and DeepSAV scores of SAVs in the human proteome, including pathogenic and benign SAVs, population-level SAVs, and all possible SAVs by single nucleotide variations. This database serves as a useful resource for research of human SAVs and their relationships with protein functions and human diseases.
As panel testing expands, more individuals with double pathogenic variants (DPVs) in cancer susceptibility genes are likely to be identified. Little is known about the effects of DPVs on cancer ...phenotype, although this information is crucial for genetic counseling and risk management. We sought to describe the cancer phenotype among individuals with DPVs in cancer susceptibility genes.
A retrospective study of individuals with DPVs identified through a single testing laboratory from 2012 to 2017 was conducted. DPV combinations were enumerated. For DPV gene combinations that occurred >10 times, cancer histories of individuals with DPVs were compared with cancer histories of controls with a single PV matched by gene.
Among 644 individuals with DPVs, combinations that included the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes occurred >10 times. There were 8883 matched controls for a single PV in these genes. The median age of first cancer diagnosis was younger with ATM+CHEK2 (43), compared with ATM (47, P = .016) or CHEK2 (47, P = .015) alone. Similar findings were observed when comparing age at first breast cancer (BC) for the ATM+CHEK2 with single-gene controls. Individuals with 2 CHEK2 PVs also were younger at first cancer diagnosis (40) compared with single CHEK2 PV controls (47, P = .0038). This difference was not driven by age at first BC diagnosis among females.
Individuals with ATM+CHEK2 or 2 CHEK2 PVs have a greater cancer burden than single gene controls. These findings can be used to counsel individuals with DPVs and their families and inform cancer screening recommendations.
Multigene panel testing now allows efficient testing of many cancer susceptibility genes leading to a larger number of mutation carriers being identified. They need to be counseled about their cancer ...risk conferred by the specific gene mutation. An important cancer susceptibility gene is PALB2. Multiple studies reported risk estimates for breast cancer (BC) conferred by pathogenic variants in PALB2. Due to the diverse modalities of reported risk estimates (age-specific risk, odds ratio, relative risk, and standardized incidence ratio) and effect sizes, a meta-analysis combining these estimates is necessary to accurately counsel patients with this mutation. However, this is not trivial due to heterogeneity of studies in terms of study design and risk measure. We utilized a recently proposed Bayesian random-effects meta-analysis method that can synthesize estimates from such heterogeneous studies. We applied this method to combine estimates from 12 studies on BC risk for carriers of pathogenic PALB2 mutations. The estimated overall (meta-analysis-based) risk of BC is 12.80% (6.11%-22.59%) by age 50 and 48.47% (36.05%-61.74%) by age 80. Pathogenic mutations in PALB2 makes women more susceptible to BC. Our risk estimates can help clinically manage patients carrying pathogenic variants in PALB2.
