Angela Peron

Objective: This study was undertaken to establish expert consensus clinical and diagnostic criteria for ring chromosome 20 syndrome using a modified electronic Delphi process. Methods: In this modified two‐round electronic Delphi consensus study, international experts rated candidate statements using a 9‐point Likert scale. Consensus was predefined as at least 70% agreement. A disagreement index assessing rating dispersion was calculated for each statement. The international expert consensus study was conducted remotely using Research Electronic Data Capture. Thirteen international experts with clinical and/or research expertise in ring chromosome 20 syndrome were invited; 12 completed Round 1, and 11 completed Round 2. Experts evaluated statements developed by a steering committee across clinical and diagnostic domains, including age at onset, seizure phenotype, comorbidities, treatment response, laboratory testing, neuroimaging, electroencephalographic findings, and genetic/genomic testing. Statements not reaching consensus after Round 1 were revised and redistributed in Round 2. Proportion of statements achieving consensus agreement was determined, and high‐agreement statements were synthesized into key diagnostic criteria. Results: Consensus was achieved for 25 clinical statements and 19 diagnostic statements, with agreement ranging from 73% to 100%. Clinical consensus emphasized normal early development before seizure onset, seizure onset most commonly between ages 4 and 8 years in mosaic cases, rapid progression to drug resistance, and recurrent nonconvulsive status epilepticus with fluctuating cognitive impairment. Diagnostic consensus highlighted the limited utility of routine laboratory testing and neuroimaging, while strongly endorsing a characteristic electroencephalographic pattern of prolonged rhythmic theta activity over frontal and temporal regions. Participants unanimously agreed that karyotype analysis is required for diagnosis and that next generation sequencing modalities cannot reliably establish diagnosis in mosaic cases. Significance: This study establishes the first internationally accepted consensus clinical and diagnostic criteria for ring chromosome 20 syndrome. These criteria provide a framework to improve recognition of this underdiagnosed epilepsy syndrome and reinforce the continued importance of cytogenetic testing in childhood onset drug‐resistant epilepsy.

We provide a comprehensive phenotypic characterization of loss-of-function (LoF) variants in WDFY3 based on the largest cohort reported to date ( n = 32). Our findings define a monogenic disorder marked by neuropsychiatric features (including autism and ADHD), mild to moderate neurodevelopmental delay, and variable brain growth – most commonly macrocephaly and in one case reduced head circumference. To investigate the effect of WDFY3 LoF we performed knockdown (KD) in the human neuroblastoma cell line SH-SY5Y and used a Wdfy3 -haploinsufficient mouse model. WDFY3 KD impaired clearance of protein aggregates and decreased protein levels of the ubiquitin-binding protein p62. Transcriptomic analyses identified dysregulation in gene networks that are primarily involved in nervous system development, neuron projection, MAPK/ERK1/2, and WNT/β-catenin signaling. This was confirmed at protein level. Neuronal cell proliferation was increased, as evidenced by elevated cell counts and proliferation markers Ki-67 and PCNA . Conversely, neuronal cell differentiation was impaired, as indicated by reduced neurite outgrowth. We show that β-catenin is downregulated, while GSK3B is upregulated. LiCl activates WNT/β-catenin signaling by inhibiting GSK3B. We thus tested LiCl treatment, which significantly increased WDFY3 expression. Moreover, in vitro treatment improved the neurite branching capacity of Wdfy3 -haploinsufficient neurons above the level of the wild type, although this specific effect appeared independent of WNT/β-catenin signaling. In sum, we expand on the phenotype related to WDFY3 LoF and provide insights into the pathophysiology using in vitro human and murine neuronal models. Our findings suggest that LiCl may serve as a potential therapeutic strategy for patients with WDFY3 LoF variants.

Fanconi Anemia (FA) is the most frequent inherited bone marrow failure syndrome. A role for the XRCC2 gene in FA was suspected in 2012 and confirmed in 2016, but only two affected individuals have been described thus far, and no long‐term follow‐up is available. Here we present two young related adults born to consanguineous parents, in whom we identified the homozygous p.(Arg215Ter) variant in XRCC2 . Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. Unlike in FA, DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected until the age of 19 and 20 years, respectively. Our report suggests that the homozygous p.(Arg215Ter) variant in XRRC2 causes a distinctive FA‐like disorder, characterized by the typical physical characteristics seen in FA, but a lack of major hematological manifestations in childhood, and the presence of a more pronounced neurodevelopmental phenotype than that seen in FA.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder–Robinson syndrome results from hemizygous loss‐of‐function variants in the spermine synthase ( SMS ) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann–Bupp syndrome results from heterozygous gain‐of‐function variants in the ornithine decarboxylase 1 ( ODC1 ) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes–Banka syndrome results from heterozygous loss‐of‐function variants in the eukaryotic translation initiation factor 5A ( EIF5A ) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi‐allelic hypomorphic variants in the deoxyhypusine synthase ( DHPS ) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi‐allelic loss‐of‐function variants in the deoxyhypusine hydroxylase ( DOHH ) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder–Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

TSPEAR (chr. 21q22.3) encodes a protein involved in tooth development and is predominantly expressed in the enamel knot. Biallelic loss of function variants in TSPEAR cause ectodermal dysplasia, tooth agenesis and sensorineural hearing loss. However, the role of TSPEAR in auditory processes is unclear. This study aimed at better delineating the allelic and clinical spectrum of TSPEAR ‐associated disorders. We identified homozygous and compound heterozygous causative variants in TSPEAR [NM_144991.3] in 11 patients from seven families. Abnormalities in tooth number and shape (conical teeth and tooth agenesis with a variable number of missing teeth) were found in all affected individuals. Maxillary retrusion was present in 6/11. Manifestations in other ectodermal‐derived organs were seen in a minority of patients. None of the individuals had hearing loss. We identified a total of 10 variants, of which seven have not been previously published, and analyzed the effect of missense variants to support their pathogenicity. Our results demonstrate that individuals with biallelic variants in TSPEAR show complete penetrance for dental manifestations, but not for other ectodermal abnormalities. TSPEAR ‐related disorder is more common than previously thought, while hearing loss is not a feature of the disease.

Different types of germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders: Schinzel-Giedion syndrome (SGS, via missense variants at a critical degron region) and SETBP1-haploinsufficiency disorder. However, due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of its roles in neurodevelopment, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remains elusive. This imposes challenges for diagnosis. Here, we present a comprehensive investigation of the largest cohort to date of individuals carrying SETBP1 missense variants outside the degron region (n = 18). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1-haploinsufficiency disorder. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding, transcription, and neuronal differentiation capacity and morphologies. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care, and aetiology of SETBP1-related disorders.

The European Certificate in Medical Genetics and Genomics (ECMGG) is the official knowledge-based, end-of-specialist training examination designed and delivered by the Union Européenne des Médecins Spécialistes – Section of Medical Genetics (UEMS-SMG). The examination is a joint venture of the SMG, the European Society of Human Genetics (ESHG), and the European Board of Medical Genetics (EBMG). Sittings have taken place in 2019 and 2021–24, and it is gaining in reputation as a high-quality, high-standard assessment. In 2024 the ECMGG underwent satisfactory appraisal by the UEMS-Council of European Specialist Medical Assessment (CESMA). This paper describes the development of the ECMGG, its structure, outcomes, and its meaning for the standards and harmonisation of the specialty of Medical Genetics throughout Europe.