Correction: ELMO2-related intraosseous vascular malformation: new cases with novel pathogenic variants, clinical follow-up and therapeutic approaches.

Primary intraosseous vascular malformation (VMPI, #606893) is an ultra-rare disorder caused by biallelic pathogenic variants in ELMO2. To date, only six families with pathogenic ELMO2 variants causing a VMPI phenotype have been described. VMPI is characterized by vascular malformations that compress the facial bones, often leading to life-threatening complications, such as massive bleeding and intracranial herniation. In VMPI, vascular malformations are progressive and there is no causal therapy available. We report on four unreported individuals with classical VMPI harbouring biallelic truncating variants in ELMO2, including a novel homozygous 25 bp duplication c.579_603dup; p.(Leu202Profs*47), detected by whole-exome sequencing. We present extensive clinical follow-up data, including a close monitoring of an individual from prenatal diagnosis onwards. Using computed tomography or magnetic resonance imaging angiography, we described the radiological characteristics of vascular malformations with fast-flow properties in the affected individuals. Additionally, we conducted a comprehensive histopathological evaluation of samples from one individual. This analysis revealed not only the similar morphological features described previously but also some atypical findings, such as increased de novo bone formation. Furthermore, we report for the first time the use of propranolol and sirolimus in VMPI. While we noted a reduction of bleeding episodes in one individual, no significant clinical improvement was observed overall in the other individuals treated with sirolimus. Moreover, sirolimus led to severe infectious complications with abscess formation in two individuals. Conversely, propranolol was relatively well tolerated, although it did not result in any notable clinical outcomes. During follow-up, one individual died due to severe bleeding.

BackgroundMaturity-Onset Diabetes of the Young (MODY) comprises monogenic, non-syndromic forms of diabetes inherited in an autosomal dominant pattern. MODY is frequently misdiagnosed as type 1 diabetes (T1D), type 2 diabetes (T2D), or gestational diabetes mellitus (GDM). Studies suggest that 50–90% of MODY cases are erroneously classified as type 1 or type 2 diabetes, and up to 5% of women with GDM may have undiagnosed MODY. However, data regarding the clinical presentation and genetic characterization of MODY in Latin American populations remain scarce. This study aimed to describe the clinical, analytical, and genetic characteristics of MODY patients initially misdiagnosed as T1D, T2D, or GDM in a Latin American tertiary care center.MethodsMedical history, clinical and laboratory data were obtained from electronic medical records to assess diagnostic accuracy and identify phenotypic patterns suggestive of MODY. Whole exome sequencing (WES) was employed to detect mutations related to monogenic variants.ResultsWe identified five patients with MODY. The median age at diabetes diagnosis was 13.6 years, while the median age at MODY diagnosis was 25.8 years. The average duration between the initial diabetes diagnosis and confirmation of MODY was 12.2 years. None of the patients presented with diabetic ketoacidosis at the onset of diabetes. All patients tested negative for islet cell autoimmunity. Of the five patients, two were initially misclassified as having T1D, two as T2D, and one as GDM. Whole-exome sequencing (WES) identified a pathogenic missense variant, c.94G>A (p.Gly32Ser), in the INS gene (MODY10) in one patient initially diagnosed with T1D. Another patient, also misclassified as T1D, carried a pathogenic missense variant, c.709A>G (p.Asn237Asp), in the HNF1A gene (MODY3). Additionally, two patients initially diagnosed as T2D were found to carry missense variants: a likely pathogenic variant, c.613G>T (p.Asp205Tyr) in the GCK gene (MODY2) and pathogenic variant, c.4135C>T (p.Arg1379Cys) in the ABCC8 gene (MODY12), respectively. The patient initially diagnosed with GDM was revealed to have a pathogenic frameshift variant, c.616dupC (p.His206Profs*38), in the NEUROD1 gene (MODY6). Based on these findings, a change in therapeutic approach was implemented.ConclusionsMODY is often misdiagnosed, leading to delays in appropriate management. Whole-exome sequencing is crucial for identifying pathogenic variants, enabling accurate reclassification and tailored therapy.

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

Phenotypic heterogeneity is a well-known feature of Familial Partial Lipodystrophy Type 2 (FPLD2) which is caused by pathogenic variants in the LMNA gene. Clinical diagnosis can be challenging in some cases. Likewise, trained physicians can report differences in body composition and clinical manifestation of FPLD2, highlighting the importance of accurate phenotyping. In this study, we aimed to identify phenotype-genotype correlations in a cohort of systematically evaluated patients with FPLD2. We retrospectively evaluated 43 patients diagnosed with FPLD2 (age 50.3±16.1 years, 79.1% women). Per pathogenic variants, patients were divided into two groups; 24 with R482Q (RQ: 55 ± 3.2 years, 70.8% women) and 19 with non-R482Q (Non-RQ: 46 ± 3.2 years, 84.2% women). Non-RQ group consisted of several pathogenic LMNA variants in exons 1, and 5 through 11. Also, DEXA parameters were studied in a subgroup of 19 patients with available assessments (in 11 RQ and 8 non-RQ patients) that were matched for age, sex and BMI. Patients in the RQ group were older when they were first diagnosed with lipodystrophy (48.6 ± 3.2 years and 37.4 ± 3.1 years, p = 0.03). Although the prevalence of diabetes, hepatic steatosis and other co-morbidities associated with metabolic control were similar in both groups at the time of the study, patients with RQ pathogenic variants were diagnosed later in life with diabetes (46.0 ± 4.2 years vs. 35 ± 3.5 years, p = 0.03) and hepatic steatosis (45.3 ± 6.9 years vs. 30.1 ± 3.7 years, p < 0.01. Although more pancreatitis episodes were reported in the RQ group (13 ± 3 vs. 2 ± 1, p = 0.02), the number of patients with a history of pancreatitis was similar across the groups suggesting the occurrence of recurrent pancreatitis episodes in selected patients with RQ pathogenic variant. Pain was a common complaint among the patients, but it was less severe in the RQ group (4.2±2.1 vs 2.3±2.0, p=0.05). In terms of body composition, patients with RQ pathogenic variants had greater bone mass (legs: 879 ± 59.3 g vs. 703.5 ± 33.7 g, p= 0.01; trunk 914.2 ± 65.5 g vs. 674.1 ± 28.0 g, p = 0.005, total body: 2643.7 ± 158.9 g vs. 2140.6 ± 78.4 g, p = 0.005) and higher fat mass in the legs (19 vs. 14%, p = 0.02). Similarly, patients with RQ pathogenic variants had less lean percentage (76 vs. 81%, p = 0.009), and accordingly, less fat-free mass percentage (80 vs. 85%, p = 0.02) in the legs. Total fat-free mass of the RQ group was also lower (66 vs. 76%, p = 0.0009). Genotype-phenotype characterization is important not only for understanding the natural history and clinical manifestation of the disease but also for establishing more accurate and precise diagnostic criteria or therapeutic approaches. Our data suggest more fat preservation in LMNA R482Q carriers, presumably leading to a later diagnosis of lipodystrophy and metabolic abnormalities. More studies are needed to confirm the differences observed in body composition.

Different pathogenic variants in the fibrillin‐1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility, and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints, and hypermuscularity. Similarly, pathogenic variants in the fibrillin‐2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2‐related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2‐related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the “tall” and “short” fibrillinopathies. The future parallel functional study of both FBN1/2‐related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.

The 5–10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10–20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.

Usher syndrome (USH), the most common form of deaf-blindness, displays extensive genetic, allelic, and phenotypic heterogeneity. The dual sensory impairment associated with this disorder makes Usher syndrome an important target for gene therapy, with dozens of published preclinical studies targeting multiple USH genes and using multiple gene therapy strategies. Nine genes have been conclusively linked to Usher syndrome; however, data on prevalence and contribution of specific genetic variants is lacking. Such information is essential to choosing a favorable target gene or therapeutic approach during clinical trial design. Here, we used large genomic databases to systematically evaluate the genomics of Usher syndrome. We ascertained pathogenic USH variants from three clinical databases and determined the occurrence of these pathogenic USH variants within: (1) a publicly available dataset including worldwide populations (GnomAD), (2) a cohort of 3,888 children without hearing loss, and (3) 637 children with hearing loss. Results show significant variability in the frequency of USH variants by gene and genetic ancestry. 1% of control subjects carry a pathogenic USH variant. Pathogenic variants in USH2A are the most prevalent, at 1 in 150 individuals (0.0062). Calculated general population prevalence for all USH subtypes is 1 in ∼29,000, indicating that 30,405 individuals in the United States and 721,769 individuals worldwide are affected. We estimate that 324 babies in the United States and 12,090 worldwide are born with Usher syndrome each year. We identify key targets for genetic therapy based on population-level prevalence including a focus on alternatives to gene replacement therapies, specifically for USH2A .

Genomic screening holds great promise for presymptomatic identification of hidden disease, and prevention of dramatic events, including sudden cardiac death associated with arrhythmogenic cardiomyopathy (ACM). Herein, we present findings from clinical follow-up of carriers of ACM-associated pathogenic/likely pathogenic desmosome variants ascertained through genomic screening. Of 64 548 eligible participants in Geisinger MyCode Genomic Screening and Counseling program (2015-present), 92 individuals (0.14%) identified with pathogenic/likely pathogenic desmosome variants by clinical laboratory testing were referred for evaluation. We reviewed preresult medical history, patient-reported family history, and diagnostic testing results to assess both arrhythmogenic right ventricular cardiomyopathy and left-dominant ACM. One carrier had a prior diagnosis of dilated cardiomyopathy with arrhythmia; no other related diagnoses or diagnostic family history criteria were reported. Fifty-nine carriers (64%) had diagnostic testing in follow-up. Excluding the variant, 21/59 carriers satisfied at least one arrhythmogenic right ventricular cardiomyopathy task force criterion, 11 (52%) of whom harbored DSP variants, but only 5 exhibited multiple criteria. Six (10%) carriers demonstrated evidence of left-dominant ACM, including high rates of atypical late gadolinium enhancement by magnetic resonance imaging and nonsustained ventricular tachycardia. Two individuals received new cardiomyopathy diagnoses and received defibrillators for primary prevention. Genomic screening for pathogenic/likely pathogenic variants in desmosome genes can uncover both left- and right-dominant ACM. Findings of overt cardiomyopathy were limited but were most common in DSP-variant carriers and notably absent in PKP2-variant carriers. Consideration of the pathogenic/likely pathogenic variant as a major criterion for diagnosis is inappropriate in the setting of genomic screening.

BACKGROUND AND AIMS ADTKD–UMOD (Autosomal dominant tubulointerstitial kidney disease–UMOD) is a rare genetic disease due to a heterozygous mutation in the UMOD gene encoding uromodulin. It is classically characterized by minimal proteinuria, slowly progressive CKD, hyperuricemia and early-onset gout. With increasing awareness and testing, pathogenic variants in UMOD are being identified more frequently although the nonspecific nature of most symptoms makes clinical diagnosis difficult. We report the surprising finding of a rare UMOD variant in 11 seemingly unrelated families referred to Sheffield or Nottingham renal genetics services over a 15-year period with undiagnosed hereditary kidney disease. METHOD The probands identified were initially referred to renal genetics services based in Sheffield and Nottingham between 2006 and 2021, where they underwent genetic testing and a comprehensive renal workup. All had a family history of ESRD. A pathogenic variant of UMOD, c.278_289delinsCCGCCTCCT was identified in 11 probands by gene or panel-based sequencing. Family members of the affected probands were invited for genetic testing and clinical follow-up. A retrospective review of all patients screened or with ESRD at both renal genetic clinics was conducted. Molecular modeling of the variant was performed using in-silico tools. RESULTS Clinical data from 60 members (11 pedigrees) was obtained. All individuals were born in the United Kingdom and of White British ethnicity. A total of 37 tested positive for the variant, 3 were negative and 19 were not tested due to being deceased (n = 13) and for unknown reasons (n = 6). The median age of ESRD was 52 (range 32, 76) years. More females had ESRD comprising 67% (20/30). Of patients with available data, 68% (30/44) had hypertension, 7.3% (3/41) had proteinuria &amp;gt;30 mg/g and 18% (7/40) had mild hematuria. A total of 11% (6/57) had experienced ≥1 episode of gout with a median onset of 42.5 (range 29–61) years. Only one patient had asymptomatic renal calculi. All patients with CKD who carried the UMOD mutation (n = 22) had hypertension, apart from two who had unknown hypertensive status (n = 1) or reflux nephropathy causing kidney scarring (n = 1). Renal histology where available (8) showed glomerulosclerosis and tubulointerstitial fibrosis. Ultrasound kidney lengths were normal or reduced and renal cysts were only occasionally detected. Molecular modeling of the variant showed structural changes in the cysteine-rich (C6) with EGFII-like Ca2+ binding domain of UMOD, predicted to disrupt disulfide-bond formation (fifth cysteine C94–sixth cysteine C106) as well as by altering the loop (93–97) between two β-sheets of EGFII domain (AlphaFold), possibly altering calcium ion binding (DeepFRI). This variant was initially reported as a recurrent mutation in four apparently unrelated families [1] and has since been noted in a further 11 families [2], all of White British ethnicity. CONCLUSION We have identified a rare pathogenic UMOD variant shared by 11 apparently unrelated families with familial ESRD within a contiguous geographical region of England. The nonspecific symptoms associated with this variant (especially the rarity of gout) were atypical from those with more classical UMOD variants leading to a delay in diagnosis. Our findings and those of others suggest that this is likely to represent a common ancestral variant rather than a recurrent variant within the UK population. 1. Smith GD, Robinson C, Stewart AP et al. Characterization of a recurrent in-frame UMOD indel mutation causing late-onset autosomal dominant end-stage renal failure. Clin J Am Soc Nephrol 2011; 6: 2766–2774. 2. Kidd K, Vylet'al P, Schaeffer C et al. Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations. Kidney Int Rep 2020; 5:1472–1485.

Additional Genetic Variants in Inherited Dilated Cardiomyopathy: Just Another Brick in the Wall?

Genetic Profile of Arteriovenous Anomalies of the Head and Neck: Implications in Progression and Therapeutic Approaches

Hereditary transthyretin amyloid cardiomyopathy

The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (BRCA1/2) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at BRCA2 (47/98), BRCA1 (24/98), PALB2 (8/51), ATM (7/51), CHEK2 (6/51) MSH6, (2/51), RAD51C (2/51) and TP53 (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for BRCA1 and MSH6 pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for BRCA2 and BRCA1 pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (p = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from BRCA1 and BRCA2, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for BRCA1/2 between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.

BACKGROUNDPediatric patients with Diffuse Midline Gliomas (DMG), H3K27M altered have a dismal prognosis and novel therapeutic approaches are urgently needed. Factors that drive development of pediatric DMG are unknown. METHODSTo determine the prevalence of germline pathogenic/likely pathogenic variants (P/LPV) in DMG, we assembled an international cohort of 252 patients with germline whole genome or whole exome sequencing data, including diffuse intrinsic pontine glioma (DIPG; n=153), from Australian, European and North American centres. RESULTSWe identified germline P/LPV in cancer predisposition genes in 7.5% (19/252) of patients, mainly homologous recombination (n=9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n=4). Germline P/LPV in mismatch repair genes (MSH2, PMS2) were found in two patients. Two patients each had two separate germline P/LPV. The prevalence of germline P/LPV was not significantly different according to age, location of DMG nor H3K27M mutational status. Furthermore, tumor profiles differed, with absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LPV compared to those without (P = 0.023). Knockdown of BRCA1 in DMG cell cultures sensitized tumor cells to PARP inhibition. Reflecting the potential therapeutic relevance of these findings, we describe one H3.3 K27M-mutant DMG patient with a pathogenic germline BRCA2 and FANCE variant and multiple recurrences, who was treated with a PARP inhibitor (olaparib) and immune checkpoint inhibitor, leading to a near complete radiological response after 4 months. CONCLUSIONOur study is the largest series to date investigating germline P/LPV in cancer predisposition genes in DMG and provides new therapeutic insights. It is expected that these germline findings will also guide cascade testing for a proband’s relatives. Our data highlight the importance of germline testing in H3K27-altered DMG patients at diagnosis.

Usher syndrome, the most common form of deaf-blindness, displays extensive genetic, allelic, and phenotypic heterogeneity. The dual sensory impairment associated with this autosomal recessive disorder makes Usher syndrome an important target for gene therapy, with dozens of published preclinical studies targeting multiple Usher syndrome genes and using multiple gene therapy strategies. Nine genes have been conclusively linked to Usher syndrome; however, data on the prevalence and contribution of specific genetic variants is lacking. Such information is essential to choosing a favorable target gene or therapeutic approach during clinical trial design. Here, we used large genomic databases to systematically evaluate the genomics of Usher syndrome. We ascertained pathogenic Usher syndrome variants from three clinical databases and determined the occurrence of these pathogenic Usher syndromevariants within: (1) a publicly available dataset including worldwide populations (GnomAD), (2) a cohort of 3888 children without hearing loss, and (3) 637 children with hearing loss. Results show significant variability in the frequency of Usher syndrome variants by gene and genetic ancestry. 1% of control subjects carry a pathogenic USH variant. Pathogenic variants in USH2A are the most prevalent, at 1 in 150 individuals (0.0062). Calculated general population prevalence for all Usher syndrome subtypes is 1 in ~29,000, indicating that 30,405 individuals in the United States and 721,769 individuals worldwide are affected. We estimate that 324 babies in the United States and 12,090 worldwide are born with Usher syndrome each year. We identify key targets for genetic therapy based on population-level prevalence including a focus on alternatives to gene replacement therapies, specifically for USH2A.