Journal of Medical Genetics

Margot, Henri; Hernandez Poblete, Natalia; Angelini, Chloé; Desforges, Julie; Bouron, Julie; Arveiler, Benoit; Rooryck, Caroline; Goizet, Cyril; Fergelot, Patricia

doi: 10.1136/jmg-2024-110336pmid: 39779312

Background FLNA loss of function manifests across a broad spectrum of phenotypes, ranging from severe prenatal onset to asymptomatic cases. Bilateral periventricular nodular heterotopia (BPNH) consistently occurs in affected individuals. This retrospective study involving French patients with BPNH evaluates the prevalence of FLNA gene dosage anomalies and investigates genotype-phenotype correlations in a large cohort of French patients with BPNH.MethodsA retrospective observational study was conducted on 391 individuals diagnosed with BPNH confirmed by brain MRI. Sequencing analysis using Sanger or next-generation sequencing was complemented by targeted array-comparative genomic hybridisation to identify copy number variants (CNVs).Results FLNA variants were identified in 40% of females and 12% of males. Among these, 87% were single nucleotide variants (SNVs), while CNVs accounted for 13%, all of which were deletions. Half of the CNVs involved a recurrent deletion spanning exons 31–48, often accompanied by a duplication of the neighbouring EMD gene. This del-dup was associated with a milder phenotype, whereas smaller de novo deletions correlated with severe outcomes. Mosaicism was also detected in three cases.Conclusion FLNA CNV analysis, particularly for recurrent deletions and mosaicism, is essential in the genetic evaluation of BPNH. Integrating CNV detection with SNV analysis improves diagnostic accuracy and enhances understanding of genotype-phenotype correlations.

Song, Yue; Xia, Yang; Peng, Ziyue; Meng, Yuhuan; Jing, Wenwen; Xie, Li; Cao, Tianhua; Zhang, Jiahui; Song, Huilin; Meng, Lingdi; Zhang, Yi; Sui, Shengbin; Mao, Di; Jia, Ying; Qiao, Shupei; Yu, Shihui; Zhang, Xue

Xiao, Yi; Tan, Yushan; Li, Chunyu; Wei, Qianqian; Jiang, Qirui; Wang, Shichan; Yang, Tianmi; Lin, Junyu; Zhang, Lingyu; Shang, Huifang

doi: 10.1136/jmg-2024-109978pmid: 39779313

BackgroundConsiderable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (OPTN) mutations, as reported in prior studies. The study aimed to elucidate the correlation between OPTN genotypes and phenotypes.MethodsOPTN gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of OPTN mutations and explore the relationship between the genotype and phenotype of patients with ALS with OPTN.ResultsA total of 33 unrelated patients with ALS with 24 rare OPTN variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of OPTN variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.ConclusionOur study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying OPTN variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.

Kishnani, Priya S; Seefried, Lothar; Dahir, Kathryn M; Martos-Moreno, Gabriel Á; Högler, Wolfgang; Greenberg, Cheryl R; Fang, Shona; Petryk, Anna; Mowrey, William R; Linglart, Agnès; Ozono, Keiichi

doi: 10.1136/jmg-2024-110383pmid: 39965917

BackgroundHypophosphatasia (HPP) is a rare metabolic disease caused by autosomal dominant or recessive inheritance of ALPL variants resulting in low alkaline phosphatase activity. The objective of this analysis was to compare HPP disease burden between patients with non-life-threatening disease in the Global HPP Registry who have one ALPL variant versus two or more ALPL variants.MethodsPatients were included if they had one or more ALPL variants identified through genetic testing and first HPP manifestations after 6 months of age. Assessments included history of HPP manifestations, Brief Pain Inventory-Short Form (BPI-SF), Health Assessment Questionnaire-Disability Index (HAQ-DI), 6-Min Walk Test (6MWT), Paediatric Quality of Life Inventory (PedsQL) and 36-Item Short-Form Survey V.2 (SF-36v2).ResultsOf 685 included patients, 568 (82.9%) had one ALPL variant, 116 (16.9%) had two variants, and one (0.1%) had three variants. Patients with two or more ALPL variants had higher proportions of skeletal (52.1% vs 32.6%), dental (73.5% vs 56.0%), muscular (36.8% vs 23.6%) and neurological (22.2% vs 8.8%) manifestations at last assessment. BPI-SF, HAQ-DI, PedsQL and SF-36v2 scores were similar between groups. Distances walked on the 6MWT were similar between groups for children. Distance walked was lower among adults with two or more variants (293 m (n=8)) than adults with one variant (466 m (n=103)), although the former group was very small.ConclusionHPP disease burden is high in patients with HPP, regardless of ALPL variant number. While prevalence of HPP-specific manifestations was higher in patients with two or more variants than those with one variant, patient-reported outcomes were similar between groups.Trial registration number NCT02306720; EUPAS13514.

Jeanne, Médéric; Ronce, Nathalie; Remizé, Solène; Arpin, Stéphanie; Baujat, Geneviève; Breton, Sylvain; Petit, Florence; Vanlerberghe, Clémence; Coeslier-Dieux, Anne; Manouvrier-Hanu, Sylvie; Vincent-Delorme, Catherine; Khau Van Kien, Philippe; Van-Gils, Julien;

Dutta, Dibyendu; Black, Jennifer; Montoya, Emily A; Burrow, Thomas Andrew; Shieh, Joseph; McGivern, Bobbi; Raymond, Michelle; Sheedy, Christina B; Smith, Scott C.; Garg, Ria

doi: 10.1136/jmg-2024-110367pmid:

Gazzin, Andrea; Reynolds, Giuseppe; Massuras, Stefania; Luca, Maria; Coppo, Paola; Carli, Diana; Piglionica, Marilidia; Martino, Stefania; Bagnulo, Rosanna; Ferrero, Giovanni Battista; Resta, Nicoletta; Mussa, Alessandro

doi: 10.1136/jmg-2024-110364pmid: 39870398

Lateralised overgrowth (LO) is characterised by the asymmetric increase in the size of any part of the body exceeding 10% compared with the unaffected contralateral one. LO is a key feature in various syndromic overgrowth disorders, such as Beckwith-Wiedemann spectrum and PIK3CA-related overgrowth spectrum (PROS). However, it can also present as isolated (ILO). Defining the aetiology of LO is critical due to the clinical implications and management strategies required for each condition. This report presents two patients who were followed up throughout childhood for ILO and were ultimately diagnosed with PROS through molecular analysis on DNA extracted from a skin biopsy, revealing the PIK3CA:c.263G>A (p.Arg88Gln) variant at a high variant allele frequency. This variant has been described in association with macrocephaly-capillary malformation syndrome but not with ILO. In conclusion, this is the first report of patients harbouring the (p.Arg88Gln) variant with a diagnosis of ILO, thus, highlighting the importance of considering ILO within the PROS and underscoring the necessity for somatic DNA testing. An early and accurate molecular diagnosis is crucial for guiding appropriate clinical management in order to ensure access to targeted therapies, emphasising the need for further research to refine diagnostic criteria and testing recommendations for ILO.

DeBose-Scarlett, Evon; Ressler, Andrew K; Friday, Cassi; Prickett, Kara K; Roberts, James W; Gossage, James R; Marchuk, Douglas A

doi: 10.1136/jmg-2024-110569pmid: 39939156

BackgroundHereditary haemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations. It is caused by inherited loss-of-function mutations in one of three genes, ENG, ACVRL1 or SMAD4. We recently showed that HHT-associated vascular malformations from liver, lung, brain and skin develop via a two-hit genetic mechanism resulting from biallelic loss-of-function mutations in either ENG or ACVRL1. Second-hit somatic mutations in SMAD4 have not been reported in HHT-associated vascular malformations. Here, we investigate a large, aggressively growing craniofacial arteriovenous malformation (AVM) from an individual with juvenile polyposis-HHT caused by a germline mutation in SMAD4.MethodsWe sequenced DNA from the AVM using a targeted gene sequencing panel to at least 1000X to identify somatic mutations that might contribute to the development of the AVM. We analysed whole genome SNP genotyping data using the algorithm Mosaic Chromosomal Alterations (MoChA) to identify somatic loss of heterozygosity.ResultsWe confirmed the germline mutation in SMAD4 (c.1610A>T, p.Asp537Val) and identified a second-hit somatic mutation also in SMAD4 (c.350dup, p.Tyr117*) that occurred in trans relative to the germline mutation. We also identified somatic loss of heterozygosity on the q arm of chromosome 18, including SMAD4. Additionally, we confirmed that the loss of heterozygosity causes loss of the wild-type allele. Thus, we identified two independent somatic alterations in SMAD4 causing biallelic loss of SMAD4 function in the AVM tissue.ConclusionWe identified biallelic loss of function of SMAD4 in a craniofacial AVM, evidence that SMAD4 also follows the two-hit mutation mechanism of HHT-associated vascular malformation pathogenesis.

Patel, Ria; Friedrich, Bettina; Sanderson, Saskia C; Ellard, Holly; Lewis, Celine

doi: 10.1136/jmg-2024-110458pmid: 39939155

BackgroundWhole genome sequencing (WGS) for paediatric rare disease diagnosis is now available as a first-line test for certain clinical indications in the Genomic Medicine Service in England. The aim of this study was to assess decisional conflict regarding WGS at the time of consent as well as parental knowledge, attitudes and satisfaction.MethodsWe conducted a multisite quantitative survey including validated measures. Surveys were sent out across seven National Health Service Trusts in England to parents of children offered WGS, within 4 weeks of their appointment.Results374/1366 survey responses were included in the final dataset. Parents were highly satisfied with their WGS appointment (mean=24.47/28), had low decisional conflict (mean=20.09/100) and felt they had received enough information and support to make an informed decision (83.9%). Parents had positive attitudes towards WGS (mean=18.17/20), and those who had discussed WGS with a genetic counsellor or genomic associate had significantly more positive attitudes than those seen by genetic consultants (p<0.001). Most parents (84.3%) strongly agreed (27.2%) or agreed (67.1%) that they had a clear understanding of what a genomic test is. Parents whose child’s condition was reported as more serious (p=0.0011) felt less conflicted about their decision.ConclusionsThe parents in this study had low decisional conflict and most felt they had made an informed decision. Further research after parents receive WGS results to assess whether any, and if so who, regrets their decision, is important.

Da Silva, Jorge Diogo; Maia, Nuno; Jorge, Paula; Sousa, Vanessa; Tkachenko, Nataliya; Soares, Ana Rita

doi: 10.1136/jmg-2024-110144pmid: 39956615

BackgroundClinicians often deal with copy-number variants of unknown significance (CNVUS) when managing neurodevelopmental disorders (NDDs). Variant classification is often complemented with textual comments, while the American College of Medical Genetics and Genomics (ACMG)/Clinical Genome Resource (ClinGen) numerical scores are rarely reported. Our aim was to determine if the application of ACMG/ClinGen scoring and inheritance/segregation studies are relevant for the reclassification of CNVUS.MethodsWe retrieved 167 CNVUS (112 duplications, 55 heterozygous deletions) from test reports of 141 patients with NDD in a 5-year period. None of those testing reports included ACMG/ClinGen scoring information for the CNVUS. One clinical and one laboratorial geneticist independently applied the ACMG/ClinGen scoring system for CNVs. Final scores/categories were assessed for potential modification when adding inheritance/segregation criteria.Results138 (83%) of the CNVUS retained the VUS classification, 14 (8%) changed to benign and 15 (9%) to (likely) pathogenic. Variants deemed benign (11 duplications, 3 deletions) mostly overlapped with ClinGen-established benign regions or were common in the general population; variants deemed (likely) pathogenic (all deletions) were either associated with unrelated autosomal recessive/later-onset autosomal dominant (AD) conditions, or with an AD NDD phenotype in a single case. Inheritance studies were available for 20 (12%) variants (17 inherited, 3 de novo), and none led to a change in classification. A simulation showed that adding inheritance information would also not change the classification of any other variant.ConclusionApplication of the ACMG/ClinGen scoring system led by itself to reclassification of 17% of VUS, despite a very low increase in diagnostic yield (1/141, 0.7%). Additionally, segregation/inheritance studies in CNVUS were mostly irrelevant in most NDD cases, challenging their routine broad application in clinical practice.