Dominant Inheritance Research Articles

Background: Bicuspid aortic valve (BAV) is a common congenital heart defect associated with serious cardiovascular complications, including thoracic aortic aneurysm and dissection (TAAD). Despite high heritability (~90%) and autosomal dominant inheritance, the genetic basis of BAV remains largely unknown. Methods: To investigate the genetic architecture of BAV, we leveraged electronic health record data linked to imputed genotyping from the VA Million Veteran Program (MVP). We developed and validated a Natural Language Processing (NLP) algorithm to extract valve leaflet morphology from echocardiographic reports and identify MVP participants with definitive BAV. We then conducted a multi-population genome-wide association study (GWAS) comparing individuals with BAV (n = 9,571) to all other MVP participants (n = 631,091) across European, African, Admixed American, and East Asian populations. Lead variants were mapped to nearby genes, followed by pathway enrichment analysis. To assess shared genetic architecture between BAV and TAAD, we calculated genetic correlation using LD score regression and performed colocalization analysis to identify shared causal loci. Results: Our NLP algorithm achieved high recall (0.955) and precision (0.984), identifying 655,762 reports (4.5%) and 83,704 patients (2.4%) with definitive BAV among 3.5 million Veterans. Of these, 9,571 had genotyping data and were included in the GWAS. Meta-analysis revealed seven loci reaching genome-wide significance (P < 5 × 10 -8 ), including two known ( PALMD, TEX41 ) and five novel loci ( PRDM6, LECT2, LPA, ADAMTSL1, ATXN2 ) (Figure 1). Enriched pathways included extracellular matrix organization, O-linked glycosylation, smooth muscle cell differentiation, and lysine degradation. BAV showed significant genetic correlation with TAAD (rg = 0.45; P = 5.64 × 10 -6 ). Colocalization analysis revealed seven shared loci between BAV and TAAD, with the strongest shared signal near PRDM6 (posterior probability ≈ 0.52). Notably, PRDM6 , which regulates smooth muscle cell differentiation, was previously implicated in a TAAD GWAS, reinforcing the possible genetic overlap between these conditions. Conclusions: Our findings identify novel candidate genes associated with BAV and support a shared genetic architecture with TAAD, providing new insights into the pathogenesis of BAV and related aortopathies while highlighting targets for future investigation.

Hereditary forms of cardiovascular disease represent a highly heterogeneous group of disorders with a prevailing autosomal dominant inheritance pattern, incomplete penetrance, and variable expressivity. Segregation analysis can help elucidate the genetic aetiology of these diseases, which may be ambiguous within individual families, thereby allowing for a more accurate risk assessment of family members. In this study, we present an alternative approach to co-segregation studies based on comprehensive clinical and molecular genetic diagnostics as part of routine testing. Next-generation sequencing was performed in 58 individuals from 12 families, including asymptomatic individuals. Pathogenic sequence variants and variants of uncertain significance of genes related to cardiopathies and arrhythmic syndromes were identified in 7 families, and their segregation within these families was observed. All willing family members were tested extensively from the start of the diagnostic process, as opposed to testing only genes found in the proband. This method enabled faster risk stratification and clinical follow-up of at-risk family members, facilitating improved disease prevention and personalised patient management.

The structure of genetic material, gene expression, and types of mutations constitute the foundation of inheritance. Autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance models explain monogenic diseases. In addition, co-dominant, polygenic, multifactorial, and epigenetic mechanisms contribute to the development of complex phenotypes. Inherited eye disorders such as retinoblastoma, Stargardt disease, Leber congenital amaurosis, red-green color blindness, and Leber hereditary optic neuropathy are discussed in relation to their genetic transmission. Understanding these genetic models and molecular mechanisms provides a scientific basis for the diagnosis and management of inherited ocular diseases.

Background: Inherited retinal dystrophies (IRDs) include a clinically and genetically diverse array of conditions resulting in progressive visual impairment. The PROM1 gene is crucial for the development and maintenance of photoreceptors. Variants in PROM1 are linked to a wide phenotypic spectra of IRDs; however, the correlation between genotype and phenotype is not fully elucidated. Comprehending these relationships is essential for enhanced diagnostic precision, patient guidance, and formulation of focused treatments. Objective: This study aims to examine the genotype–phenotype associations in patients with PROM1-associated IRDs. Clinical variability and inheritance patterns linked to different pathogenic variants are examined, aiming to clarify their different behaviors. Methods: We performed a retrospective investigation of patients identified as affected by PROM1-related IRDs. Thorough ophthalmologic assessments, including retinography, fundus autofluorescence, optical coherence tomography (OCT), and electrodiagnostic testing (EDT), were conducted. Genetic testing was performed via targeted gene panels or whole-exome sequencing. Variants were categorized based on ACMG criteria, and inheritance patterns were determined by familial segregation analysis. Clinical characteristics were analyzed among genotypic groups to ascertain potential phenotype–genotype relationships. Results: All patients had pathogenic or likely pathogenic PROM1 mutations. Both autosomal dominant and autosomal recessive inheritance patterns were identified. Dominant pathogenic variants were predominantly linked to late-onset cone-rod dystrophy or macular dystrophy, whereas biallelic variants frequently resulted in early-onset severe rod–cone dystrophy characterized by fast vision deterioration. A group of patients with the same genotypes displayed significant phenotypic variability, indicating the potential impact of modifier genes or environmental influences. Truncating mutations in the N-terminal region were significantly associated with earlier illness onset and greater functional impairment. Conclusions: PROM1-related IRDs demonstrated significant clinical and genetic heterogeneity, with the route of inheritance and type of variant affecting disease severity and progression. Our findings underscore the significance of thorough genotypic and phenotypic characterization in afflicted individuals. A deeper comprehension of PROM1-related IRD disease pathways can enhance prognosis, direct clinical care, and facilitate the advancement of genotype-based therapy strategies.

Multiple epiphyseal dysplasia (MED, OMIM #600969) is sometimes a mild skeletal dysplasia with diverse clinical findings, including early-onset osteoarthritis and short stature. Radiographic surveys can identify delayed epiphyseal ossification and cartilaginous changes. Due to genetic heterogeneity in MED, with dominant or recessive inheritance, molecular testing is essential for its diagnosis. The clinical manifestations, the results of laboratory examinations, and genetic analysis of a 14-year-old Pakistani male with MED are reported. Here we present a male patient with type-1 diabetes and hypothyroidism with bilateral knee effusions, right knee flexion contracture, and chronic arthralgias in his elbows and wrists. Given his symptomatology, a diagnosis of juvenile idiopathic arthritis (JIA) was initially suspected. Radiographs revealed sclerotic changes and fragments in the femoral and tibial epiphyses, suggesting destructive arthropathy. Genetic testing identified a COL9A3 variant (c.148-1G>C), as well as CTLA4 deficiency. The COL9A3 gene produces type IX collagen, and mutations in this gene can disrupt collagen folding or its interaction with other cartilage components. Complications include joint damage and early osteoarthritis, possibly requiring surgery. To date, only three COL9A3 splice-site mutations have been linked to MED. Our patient's splicing variant (c.148-1G>C) is novel and is likely causative, based on similar pathogenic mutations. Our patient presented with symptoms suggestive of JIA, but radiographic findings were inconsistent with this diagnosis. Genetic testing revealed a new pathogenic splicing variant in the COL9A3 gene, confirming MED. This case highlights the importance of early molecular testing if radiographic sclerotic changes are seen in the epiphyses due to the clinical and genetic heterogeneity of MED.

Neurofibromatosis (NF) is characterised by multiple skin lesions distributed across the body and follows an autosomal dominant inheritance pattern. There are two main subtypes: NF type 1 (NF1) and NF type 2 (NF2), each with distinct clinical features. NF1 typically presents with numerous cutaneous neurofibromas, café-au-lait spots, plexiform neurofibromas, Lisch nodules, freckling in the axillary or inguinal regions, and optic gliomas. In contrast, NF2 is marked by bilateral vestibular schwannomas and central nervous system tumours such as meningiomas and ependymomas. A 69-year-old male presented with a swelling on his back. He had a malignant tumour that had transformed from plexiform NF to neurofibrosarcoma. A wide-excision biopsy of the swelling was done and a Malignant Peripheral Nerve Sheath Tumour (MPNST) was given as a diagnosis on Histopathological Examination (HPE). He underwent surgery for excision of the swelling. The patient had undergone Contrast-Enhanced Computed Tomography (CECT) of the thorax, abdomen and pelvis, showing cystic bronchial changes in the lower lobe and minimal in the posterior segment of the right lower lobe. Also, there was evidence of a large heterogeneous enhancing lobulated soft tissue density lesion in the subcutaneous plane of the neck and upper back. NF can be prevented from progressing if the malignant change is identified early. Surgical excision is the primary therapy; nevertheless, there is a greater chance of local recurrence, particularly in those suffering from NF1. The patient had undergone wide local excision with vacuum-assisted closure, which was followed by skin grafting.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to progressive muscle weakness and paralysis. Approximately 10% of ALS cases are familial (FALS), with the VAPB gene's P56S pathogenic variant being notably prevalent in Brazilian families, contributing to the rare ALS8. This variant progresses more slowly than typical ALS, with distinct clinical features.To identify VAPB gene pathogenic variants in Brazilian FALS patients, particularly the P56S pathogenic variant associated with ALS8 and explore its clinical presentation and progression.Twelve FALS patients from 12 unrelated families in Rio de Janeiro were included in the study between 2023 and 2024. Clinical, laboratory, and electrophysiological data were reviewed. Collection of DNA samples happened via oral swabs, and VAPB gene sequencing was performed to identify pathogenic variants, specifically the P56S variant linked to ALS8.There were 3 cases of the P56S pathogenic variant, all presenting ALS8 with symptom onset in the lower limbs and slower disease progression. A family with 11 affected members across four generations showed an autosomal dominant inheritance pattern, with varying survival rates, highlighting its clinical variability.The present study underscores the importance of genetic screening for ALS subtypes, particularly ALS8, in Brazil. Identifying the P56S pathogenic variant enhances our understanding of ALS's genetic diversity and clinical presentation, offering a foundation for improved diagnostic practices and personalized care.

Alagille syndrome is a genetic disorder with an autosomal dominant hereditary pattern. Clinical manifestations include craniofacial, ocular, cardiac, hepatic, renal, vascular, and skeletal abnormalities with varying phenotypic penetrance; therefore, treatment would be targeted to the affected organs. A successful pregnancy in this pathology is uncommon and depends on the maternal features, particularly those that involve the cardiovascular and hepatobiliary systems. The objective of the manuscript is to present the case of a 24-year-old pregnant woman with a diagnosis of Alagille syndrome, her therapeutic challenge, and associated conditions.

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with autosomal dominant inheritance, caused by the abnormal expansion of the CTG triplet in the DMPK gene. Biomarker discovery in DM1 is crucial for monitoring disease progression. We performed RNA sequencing on blood, skin and muscle samples from the same patients to assess splicing events. Mis-splicing events were identified using the Mann-Whitney U rank-sum test, and per cent spliced in for exons was correlated with repeat expansion size using Spearman's correlation. We also examined the relationship between mis-splicing and disease severity through Fisher's exact test and correlation analyses. We identified 937, 384 and 1216 mis-splicing events in muscle, blood and skin, respectively. Of these, 52 exons in muscle and 10 in blood correlated with estimated progenitor allele length (false discovery rate (FDR) <0.1), but none in skin. Notably, nine exons in blood correlated with total muscle mis-splicing (FDR<0.05), suggesting their potential as biomarkers of severity. This is the first study to identify splicing dysregulation in blood and skin in patients with DM1 and identify novel potential blood-based mis-splicing biomarkers for disease severity. The correlation between several blood exons and the muscle splicing dysregulation indicates that blood-based biomarkers can be valuable for assessing disease severity, monitoring disease progression and evaluating treatment efficacy. Larger sample sizes may be necessary to clarify the relationship between mis-splicing and disease severity.

Background: Variants in ADIPOQ may affect gene expression and serum adiponectin levels (SAL), contributing to the development of metabolic syndrome (MetS) components and cardiometabolic disorders in Mexican adolescents. Aim: To evaluate the association of the genetic variants rs266729, rs822396, rs2241766, and rs1501299 in ADIPOQ, their haplotypes, and SAL with MetS components and cardiometabolic parameters in adolescents from western Mexico. Materials and Methods: A total of 494 adolescents from Jalisco, Mexico, aged 10-17 years, were studied. The biochemical and clinical characteristics of cardiometabolic disorders were diagnosed based on age-, sex-, and population-specific percentiles. Peripheral blood samples were obtained. Serum was separated and SAL were measured by ELISA. DNA was extracted and genotyped using real-time polymerase chain reaction for allelic discrimination. Hardy-Weinberg equilibrium was assessed, and associations were analyzed using logistic regression and Spearman correlations, with a 95% statistical confidence level. Results: SAL were lower in adolescents with MetS (P = 0.03) and low high-density lipoprotein (P = 0.01). The rs266729G allele was associated with very low-density lipoprotein >30 mg/dL in the additive inheritance model [AIM; odds ratio (OR) = 1.59, 95% confidence interval (CI) = 1.01-2.53, P = 0.04], dominant inheritance model (DIM; OR = 2.26, 95% CI = 1.07-4.73, P = 0.03), and codominant inheritance model (OR = 2.23, 95% CI = 1.03-4.81, P = 0.04). The rs822396G allele was associated with decreased SAL in AIM (OR = 5.00, 95% CI = 1.69-14.7, P = 0.004) and DIM (OR = 5.23, 95% CI = 1.41-21.6, P = 0.01). The rs2241766G allele (recessive model) was associated with increased alanine aminotransferase levels (OR = 3.73, 95% CI = 1.10-12.6, P = 0.03) and correlated with higher SAL (R = 0.202, P = 0.045). In controls, the haplotype rs822396-rs2241766-rs1501299 is in linkage disequilibrium (D' = 1), but the correlation is low (R2 < 0.1), while in MetS adolescents, D' was incomplete. Several haplotypes were associated with cardiometabolic parameters. Conclusion: The variants in ADIPOQ, are associated with MetS and low SAL. The rs822396G allele appears to be a key factor for low SAL and its association with cardiometabolic parameters. The rs2241766T allele was linked to low SAL and clinical characteristics of MetS.

Disclosure: V. Rivera-Hernandez: None. I. Singh: None.Familial partial lipodystrophies (incidence of 1 in 1 million people) are a group of disorders of selective adipose tissue loss that can be caused by Autosomal dominant or autosomal recessive inheritance. Familial partial lipodystrophy (FPL) type 2 (also called Dunnigan lipodystrophy) is the most common form and results from a missense mutation of Lamins A and C. Individuals have normal adipose tissue distribution during childhood, with gradual loss of adipose tissue that occurs at or after puberty at the arms, legs and trunk, and accumulation at the face, neck, and upper back. FPL is also characterized by the appearance of hypertrophic muscles and metabolic disorders including insulin resistance, hypertriglyceridemia, and hyperandrogenism. Sertoli cell tumors of the ovary (incidence of < 0.5%) are a rare cause of hyperandrogenemia. There are no published case reports of Sertoli cell tumor of the ovary in an individual with FPL as we now describe. A 21-year-old female with history of polycystic ovarian syndrome (PCOS) presented for evaluation of PCOS and concern for excess cortisol levels. Diagnosed with PCOS 5 years earlier by Gyn. Reported excess hair growth at the chin, lower abdominal area, and upper back, anterior scalp hair thinning, round face, and “buffalo hump”. Menarche occurred at age 11, two years after which her periods became irregular, skipping 2-3 timer per year. She is of Polish and German descent and her sister also has a history of PCOS. PCOS was managed with OCP, spironolactone and metformin. On physical exam, was noted to have some facial rounding, hirsutism, hair thinning, mildly coarse facial features, and wide neck. No dorsocervical fad pad. She had markedly muscular extremities. Additional history revealed that her sister also has a similar muscular physique without exercise training. Blood work yielded triglycerides 314 mg/dL (<150 mg/dL), total testosterone 552 ng/dL (2-45 ng/dL), free testosterone 149.0 pg/dL (0.1-6.4 pg/dL), sex-hormone binding globulin 11 nmol/L, insulin at 32.7 uIU/mL, and DHEA-s, 24 H urinary cortisol, IGF-1, TSH, Free T4, A1c and metabolic panel were normal. Transvaginal pelvic ultrasound revealed a mildly hyperechoic 3.2 cm circumscribed nodule in the left ovary suspicious for a Sertoli/Sertoli-Leydig cell tumor. MRI done for further evaluation showed a 3 cm lesion in the left ovary with isointense signal on T1, intermediate signal on T2; postcontrast images revealed a homogeneous enhancement. Patient was referred to gynecology oncology and underwent left salpingo-oophorectomy. Pathology showed a 2.9 cm well circumscribed Sertoli cell tumor. The possibility of adipose tissue re-distribution and increased musculature was evaluated further, and the patient has been diagnosed with FPL type 2.The case highlights a rare cause of hyperandrogenism in a patient with FPL type 2. It is unknown if there are any associations between these two rare diseases.Presentation: Monday, July 14, 2025

Disclosure: T. Shkeleva: None. S. Kalinchenko: None. A. Tsybulsky: None. N. Igor: None. A. Andreeva: None.The Association Between Genotypes of Increased and Decreased Type 2 5α-Reductase Activity and the Risk of Early-Onset Prostate CancerIntroduction. There is conflicting evidence regarding the significance of genetic variants in SRD5A2 (type 2 5α-reductase) for the risk of prostate cancer. These genetic markers alter the efficiency of dihydrotestosterone synthesis from testosterone, affecting not only prostate function but also male health and aging. However, the influence of SRD5A2 genotype combinations on prostate cancer risk remains understudied, and research rarely accounts for the age of disease onset. Objective: This study aimed to investigate the association between SRD5A2 (steroid-5α-reductase type 2 enzyme) genotypes—linked to increased or decreased activity—and the risk of prostate cancer in patients under 55 years of age. Patients and Methods. This case-control study included 90 participants from Russia: 45 patients diagnosed with prostate cancer before age 55 and 45 healthy men aged 55-70 without prostate cancer. Participants completed questionnaires based on the American Society of Clinical Oncology (ASCO) criteria to exclude hereditary prostate cancer cases. Genotyping was performed for two SRD5A2 variants: V89L (rs523349)—associated with reduced enzyme activity. A49T (rs9282858)—associated with increased enzyme activity. Genotyping was conducted using the Allele company’s pyrosequencing system. Genotype/allele frequencies and haplotype analysis were determined using the SNPator web tool. Additional statistical comparisons of clinical data and SNPs were performed using PASW Statistics 15. Results: The SRD5A2 V89L (rs523349) variant (reduced enzyme activity) was associated with a higher risk of prostate cancer in patients under 55 (OR = 1.58, 95% CI: 0.77-3.64) under a dominant inheritance model (GG vs. GC+CC). The minor allele C (reduced activity) was more frequent in the prostate cancer group (49%) compared to NCBI European population data (35%). The SRD5A2 A49T (rs9282858) variant (increased activity) was more prevalent in the control group, but due to low allele frequency, this association was not statistically significant. Haplotype analysis revealed that participants with low-activity SRD5A2 haplotypes (GGCC+GGGC) had higher odds of early-onset prostate cancer (OR = 1.44, 95% CI: 0.62-3.33) compared to normal/high-activity haplotypes. Conclusions: SRD5A2 genotypes associated with normal or increased type 2 5α-reductase activity—and their combinations—were not linked to a higher risk of prostate cancer in patients under 55 years old.Presentation: Sunday, July 13, 2025

Disclosure: N. Mangam: None. P. Deb: None. S. Devireddy: None. S. Nalla: None. K. Nutakki: None. T. Nayani: None.Background: Maturity-onset diabetes of the young (MODY) is most prevalent monogenic diabetes,i.e;1-5% of all diabetes cases. Most of the MODY cases are initially labelled as T1DM or T2DM based on response to insulin or oral hypoglycemic agents respectively. Diagnosing MODY is important for Precision Medicine approaches to improve quality of life. Next-generation sequencing has made genetic diagnosis affordable. Here we report an interesting case of genetically proven MODY-5 with HNF1B gene deletion. Clinical Case: A 23 years male who is a known case of diabetes mellitus since 5 years, was admitted with abdominal pain, vomiting and uncontrolled blood glucose since 6 months. He had history of orchidopexy for right undescended testes at 8 years of age and cystoscopic deroofing of seminal vesical cyst at 21 years of age. Father had T2DM at 51 years. On examination vitals were stable, BMI was 13.6 kg/m2 (underweight), no acanthosis, SMR- Tanner stage 4. Systemic examination was normal. Laboratory investigations showed RBS-280mg/dl, HbA1c-9.7%, ABG - no acidosis (pH-7.49), liver function tests- elevated total and direct bilirubin (TB-2mg/dl, DB-1.68mg/dl), elevated transaminases (SGPT-195 IU/L, SGOT- 89 IU/L) and alkaline phosphatase (251 U/L), amylase was 39 U/L, lipase was 6.4 U/L, urine ketones were negative. Autoimmune hepatitis panel and hepatitis B and C were negative. CECT Abdomen showed dorsal pancreatic agenesis and bilateral Bosnaik type 1 renal cortical cysts. Anti-GAD antibodies were negative, C-peptide was 0.8 ng/ml and fecal elastase was low. In view of young onset diabetes, agenesis of dorsal pancreas, right cryptorchidism, renal cortical cysts, cyst in seminal vesical and liver dysfunction- considered MODY-5. Whole exome sequencing revealed HNF1B gene deletion in chromosome 17. On evaluation magnesium was low (1.2 mg/dl) with high (7.5%) fractional excretion of Mg. We have treated with basal-bolus regimen of insulin and magnesium supplementation. Gastroenterologist has advised pancreatic enzyme replacement therapy and abdominal symptoms were considered functional. Psychiatrist has diagnosed depression and advised anti-depressants. He improved symptomatically, gained weight and is having good glycemic control. Conclusion: MODY-5 is caused by heterozygous variants in HNF1B gene, with autosomal dominant inheritance and 40% of HNF1B variants are de novo. In any young-onset (<35 years) diabetes with negative islet auto-antibodies and c-peptide >200pmol/L (0.6ng/ml), MODY should be suspected. Surveillance of extra-pancreatic phenotypes like chromophobe-type renal cell carcinoma (annual abdominal USG), genetic testing and family counseling are essential. In our case pancreatic imaging helped in diagnosis, as mutations in HNF1B result in aplasia of pancreatic body and tail. Therefore pancreatic imaging could help guide molecular and genetic investigation.Presentation: Monday, July 14, 2025

Disclosure: M.I. Chiamolera: Consultant of Fleury Group. G.M. Spolador: Fleury Group. J.V. Lima: Consultant of Fleury Group. P. Saddi-Rosa: Fleury Group. R.M. Biscolla: Consultant of Fleury Group. S.S. Maeda: None.Background: Hypophosphatasia (HPP) is a rare disorder caused by variants in the ALPL gene, that encodes the tissue-nonspecific alkaline phosphatase protein (TNSALP), an enzyme involved in the dephosphorylation of a wide range of substrates. Mild HPP is caused by a functional loss of one of the copies of the ALPL gene, leading to autosomal dominant inheritance. Clinical Case: A 8-year-old male patient referred for evaluation of growth delay and low body weight. Initial tests were consistent with HPP: low alkaline phosphatase (ALP) level of 88 U/L (reference range: 142-355 U/L), elevated B6 levels of 75.7 ng/mL (reference range: 8.7 – 27.2 ng/mL). However, the patient showed no signs of rickets. Cranial tomography and skull radiographs suggest a beaten copper appearance. The patient´s father, paternal grandmother and paternal aunt also presented low ALP levels, and the paternal aunt also had short stature. Notably, none of the family members exhibited dental loss. Given the clinical presentation and family history, a genetic panel was requested for further investigation into potential bone fragility disorders. Next-generation sequencing (NGS) identified a novel probably pathogenic variant in the ALPL gene (c.944_946del: p.Val315del) in heterozygous form. Interestingly, the same variant was found in the patient´s father, grandmother and aunt suggesting a possible autosomal dominant inheritance pattern. Conclusion: Further clinical follow-up, including radiographic and biochemical monitoring, along with genetic counseling, is warranted. This case highlights the importance of considering HPP in the differential diagnosis of pediatric patients with growth delay, low stature, and low alkaline phosphatase levels, even in the absence of classic features such as rickets or dental abnormalities.Presentation: Sunday, July 13, 2025

Abstract Background and Aims Autosomal dominant tubulointerstitial kidney disease (ADTKD) encompasses a group of hereditary kidney disorders characterized by tubulointerstitial fibrosis. These conditions typically follow an autosomal dominant inheritance pattern and are subclassified based on their genetic cause when identified. Pathogenic variants in UMOD, MUC1, REN, HNF1B, and SEC61A1 have been implicated in ADTKD pathogenesis. Advances in molecular diagnostics have improved genetic identification, though the true prevalence is likely underestimated. We present a cohort of ADTKD patients identified in the Nephrogenetics’ Clinic of our department between 2010 and 2024. Method Patients with chronic kidney disease (CKD) of unknown cause and undefined phenotype, or those exhibiting a renal phenotype suggestive of chronic interstitial nephritis, particularly with a family history of similar CKD, were referred to the Nephrogenetics’ Clinic for ADTKD investigation. Genetic testing methods evolved over time: Before 2015, Sanger sequencing was used. Since 2015, a stepwise genetic approach was used: (1) next-generation sequencing (NGS) for UMOD, REN, HNF1B, and SEC61A1; (2) if negative, targeted analysis for the insertion of a single cytosine in the variable-number tandem repeat (VNTR) sequence of MUC1; (3) if still negative, multiplex ligation-dependent probe amplification (MLPA) was performed to detect HNF1B deletions (P241-D2 kit, MRC-Holland). For patients with CKD and undefined phenotype, broader NGS panels for CKD were applied. Negative results underwent periodic re-evaluation, including deeper phenotyping when possible, and re-analysis using expanded gene panels, whole-exome sequencing (WES), or additional methods in reference laboratories. Pre-test genetic counseling was conducted by a nephrologist, while post-test counseling was performed jointly by a nephrologist and a geneticist, particularly for family screening and segregation studies. Results Among 35 families studied, a confirmed genetic diagnosis was obtained in 15 (43%), identifying 42 patients with ADTKD. The implicated variants were: MUC1: 5 families (18 patients); UMOD: 4 families (11 patients, all diagnosed via Sanger sequencing); HNF1B: 5 families (12 patients); REN: 1 patient with biallelic REN mutations (heterozygous). Four families presented with an undefined phenotype: two families underwent CKD panel testing due to young age at onset; two families had a cystic kidney phenotype and were tested using a cystic kidney disease panel. Notably, all these families harbored pathogenic or likely pathogenic HNF1B variants. One family underwent additional PacBio sequencing for MUC1 at a reference laboratory, leading to the identification of the dup60A variant in MUC1. Re-analysis of negative results led to the identification of pathogenic variants in two additional families: COL4A3 (heterozygous) in 1 family (2 patients); SDCCAG8 (homozygous) in 1 family (2 patients). Likely pathogenic variants were identified in: PAX2 in 1 family (3 patients); PKD1 in 1 family (3 patients); COL4A5 in 1 family (3 patients). Studies are ongoing in two families, while the remaining negative cases will undergo re-evaluation. Additionally, segregation studies are in progress for three families to assess the pathogenicity of variants in: UMOD (1 family, at least 2 patients); HNF1B (1 family, 2 patients); a family with CKD (3 patients) where the index patient carries VUS in both HNF1B and UMOD. Conclusion A genetic diagnosis of ADTKD was established in 43% of the families studied, and genetic CKD was confirmed in 57% of the families. MUC1 and UMOD were the most prevalent genes associated with ADTKD, though a significant number of cases involved HNF1B (mostly CNVs). Re-analysis of initially negative results increased the diagnostic yield for ADTKD and genetic CKD with an ADTKD-like phenotype. These findings suggest that broader gene panels as a first-line approach may enhance diagnostic accuracy. Additionally, the limitations of NGS and WES in detecting MUC1 and HNF1B variants underscore the importance of collaboration with specialized reference laboratories for ADTKD diagnosis.

Abstract Background and Aims Autosomal dominant tubulointerstitial kidney disease MUC1 (ADTKD-MUC1) is a rare genetic cause of renal impairment resulting from specific frameshift variants in the coding variable number tandem repeats (VNTR) of the MUC1 gene. ADTKD-MUC1 is characterized by progressive loss of kidney function leading to ESRD, histological evidence of tubular atrophy and interstitial fibrosis and an autosomal dominant inheritance pattern. Due to its repetitive nature and high GC content, there is great difficulty in detecting pathogenic variants in MUC1 VNTR using common methods such as exome or targeted sequencing. VNtyper is a new bioinformatics tool designed to genotype MUC1 VNTR using short-read sequencing data for reliable detection of pathogenic variants in this region. In this study, we used VNtyper for analysing exome data of large cohort of Irish renal patients in order to (i) validate its performance, (ii) explore its ability to reanalyse patients with chronic kidney disease (CKD) and (iii) examine the presence of pathogenic MUC1 VNTR variants in other renal disorders such as polycystic kidney disease (PKD). Method Patients were recruited via the Inherited Kidney Disease Clinic at Beaumont Hospital, Dublin, Ireland. Detection of pathogenic variants in MUC1 VNTR was performed by processing and analysing whole exome sequencing (WES) and targeted sequencing (TS) data of the patients using the VNtyper software. The performance of VNtyper was validated by testing samples from diagnosed ADTKD-MUC1 patients (n = 6) whose pathogenic variants were identified previously by the Snapshot method. We tested a cohort of 522 non-cystic CKD patients and 366 cystic kidney disease patients through a systematic scan by VNtyper. Results The VNtyper validated the results of the six ADTKD-MUC1 patients showed that they were all heterozygous carriers of a same pathogenic frameshift insertion in MUC1 VNTR. These findings are identical to the results of the Snapshot test conducted independently for these patients and are a complete replication of them. Among the 522 CKD patients reanalysed by VNtyper, four had heterozygous pathogenic frameshift insertions in the MUC1 VNTR. Clinically, the symptoms of these patients are consistent with those of ADTKD-MUC1. Among the 366 cystsic kidney disease patients screened by the VNtyper, four were found to carry heterozygous frameshift insertions in the MUC1 VNTR. Conclusion Until now, for many renal patients, their genomic testing for pathogenic variants in the MUC1 VNTR was difficult. The results of this study strengthen the reliability of the use of VNtyper and demonstrate its great potential for reanalysing short-read sequencing data for the diagnosis of ADTKD-MUC1 patients and for exploring the possible role of MUC1 in other kidney disorders.

BackgroundAuditory neuropathy (AN) represents a clinical manifestation of OPA1-related diseases. The diagnostic process of these diseases is challenging owing to the broad spectrum of intermediate phenotypes and diverse inherited patterns. The aim of this study was to comprehensively delineate the feature of OPA1-related patients in a Chinese AN cohort, encompassing the incident rate, inherited pattern, detailed audiological characteristics, and genotype-phenotype correlation.MethodsBetween 2003 and 2020, 452 unrelated probands with a diagnosis of AN were referred to our laboratory for molecular genetic investigation with high-throughput sequencing. Sanger sequencing was performed on the probands and their parents to verify the genetic results. Patients diagnosed as AN by clinical evaluation, auditory brainstem responses, otoacoustic emission and/or cochlear microphonic. Comprehensive auditory evaluations were conducted on OPA1-related patients, and some of them were performed a follow-up study.ResultsWe identified seven probands (1.55%, 7/452) with OPA1 variants in seven unrelated families, demonstrating distinct genetic patterns, including one family with rare autosomal recessive (AR) inheritance, six families with autosomal dominant (AD) inheritance (three were AD de novo). The AN phenotype was observed in all patients prior to the second decade of life, with AN serving as the initial presenting symptom in two patients. Additionally, probands with the rare AR inheritance exhibited a more severe phenotype. A total of eight OPA1 variants were identified, including a novel variant c.2013 + 5G > C. The GTPase domain of OPA1 exclusively harbored missense variants, and 85.71% (6/7) of the patients carried one of missense variants in OPA1. The observed phenotypes exhibited a broad spectrum of manifestations, encompassing vestibular dysfunction and developmental delay, with varying degrees of hearing loss. Among the seven patients, four exhibited severe to profound hearing loss. The annual rates of hearing loss at the frequencies of speech were 2.74 dB/year for one patient, who underwent a 10-year-old follow-up.ConclusionOur results indicated the distinct genetic patterns and variable phenotypic characteristics of OPA1-related AN in the Chinese population. The audiological features of OPA1-related patients were comprehensively described as exhibiting AN. We identified one novel splicing variants that expand the genetic spectrum of OPA1 variants in AN.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13023-025-04040-4.

Hereditary spherocytosis (HS) is a genetic hemolytic disorder primarily characterized by hemolytic anemia, jaundice, splenomegaly, and frequent complications, including cholelithiasis, accompanied by the presence of spherocytes in the peripheral blood. This disorder predominantly follows an autosomal dominant inheritance pattern; however, certain cases exhibit an autosomal recessive mode of inheritance. HS is the most prevalent disorder associated with defects in the red blood cell membrane. Primary myelofibrosis (PMF), a chronic myeloproliferative neoplasm (MPN) characterized by splenomegaly resulting from extramedullary hematopoiesis, is associated with the JAK2 V617F mutation. Currently, there are no documented instances of co-occurrence of HS and PMF in the literature. We report the case of a 37-year-old male who experienced recurrent abdominal distension and splenomegaly over the past decade, along with elevated platelet counts over the past nine years. The patient tested positive for the JAK2V617F mutation, and bone marrow smears revealed the presence of teardrop-shaped erythrocytes. Peripheral blood smears indicated the presence of approximately 20% of spherocytes. The morphology of the bone marrow biopsy specimen was consistent with an MPN, classified as MF-2 grade. The highly specific eosin-5’-maleimide binding assay demonstrated a reduced mean fluorescence intensity of 25.73%. The patient was managed with aspirin and ruxolitinib and continued to be monitored through follow-up evaluations.

ABSTRACT Corticobasal syndrome (CBS) is a rare neurodegenerative disorder characterized by asymmetric motor symptoms, cognitive impairment, and cortical dysfunction. While CCNF gene mutations have been reported in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), their role in CBS spectrum remains unexplored. This study aimed to investigate a 48-year-old patient of South Asian origin, presenting with progressive cognitive decline, behavioral disturbances, and asymmetric motor symptoms characteristic of overlap CBS syndrome. Detailed cognitive and behavioral assessments were conducted, along with brain imaging and whole-exome sequencing. Structural modeling was performed to assess the functional impact of the novel CCNF variant. The family history indicated an autosomal dominant inheritance pattern of progressive cognitive decline, further suggesting genetic predisposition. Brain imaging revealed asymmetric atrophy and hypometabolism in the left temporoparietal and prefrontal regions. Genetic analysis identified a novel heterozygous missense variant (p.Met394Leu) in the CCNF gene. Structural modeling and in-silico prediction tools suggested deleterious effects, though its functional significance remains uncertain. The study reports a potential link between CCNF variants and CBS in a South Asian family, expanding the genetic spectrum of overlap CBS. While the findings suggest potential pathogenicity, further research is required to confirm this association and elucidate the underlying mechanisms.

Enlarged vestibular aqueduct (EVA), the most prevalent inner ear malformation causing hearing loss (HL) in various populations, is predominantly genetically mediated. Despite advancements in genetic diagnostics, the comprehensive phenotypic and genotypic spectrum of EVA remains insufficiently characterized. To characterize the natural history, clinical outcomes, phenotype, and genotype of EVA. This single-center, longitudinal, retrospective cohort study was conducted from March 2003 to October 2022, with follow-up until July 1, 2024. Patients with EVA who were seeking medical advice at the Chinese PLA General Hospital were included. This study presents a 21-year longitudinal analysis of Chinese patients with EVA, providing a systematic analysis of the natural history, phenotypic diversity, and molecular etiology of EVA. Of 2774 patients, 1453 (52.4%) were female individuals, and the median (range) age was 8 (4 months to 45 years) years. This study identified that 124 of 341 patients (36.36%) with EVA received passing newborn hearing screening results, while 375 of 597 (62.8%) received a diagnosis through combined audiological and radiological assessments. Recurrent vertigo (256 of 597 [42.9%]) and goiter (38 of 597 [6.4%]) were common comorbidities. Genetic analysis revealed that 2661 of 2774 patients (95.9%) carried biallelic SLC26A4 variants, with 70 (2.5%) attributable to copy number variants and 13 (0.5%) to a deep-intronic variant (c.304 + 941C>T) that affected splicing. A de novo heterozygous FOXI1 variant (c.483_485delCAA) was identified in an EVA family, indicating an autosomal dominant inheritance pattern. A stepped genomic analysis strategy was associated with an improved molecular diagnosis rate of 95.9%, highlighting the necessity of comprehensive genetic testing beyond traditional coding regions. The results of this cohort study underscore the importance of periodic hearing surveillance and tailored genetic counseling for patients with EVA, offering substantial implications for prevention, management, and future gene therapy approaches. This study provides an extensive phenotypic and genotypic characterization of EVA, potentially advancing an understanding of its molecular underpinnings and clinical heterogeneity.