Biomedical subjects

Rebecca Buchert

Publications and source records attributed to Rebecca Buchert.

4 recordsLinked to original sources

PubMed2026

Expanding the genotypic and phenotypic spectrum of PGAP1 deficiency: clinical and functional insights from 15 patients.

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are essential for neuronal development, synaptic organization and signaling. Defects in GPI-anchor biosynthesis or remodeling cause rare neurodevelopmental disorders, including post-GPI attachment to proteins 1 (PGAP1) deficiency. PGAP1 encodes an inositol deacylase required for GPI-anchor remodeling and appropriate trafficking and membrane localization of GPI-APs. Loss of PGAP1 function disrupts GPI-AP processing, but the clinical spectrum remains incompletely defined because reported cohorts are small. We report 15 individuals with biallelic PGAP1 variants from 11 unrelated families identified through international collaboration. Clinical information was collected using a standardized phenotyping questionnaire and review of available clinical records. The most frequently recorded features were developmental delay or intellectual disability, motor developmental delay, speech impairment, facial dysmorphism, hypotonia and seizures. Independent walking was clearly recorded in a minority of individuals, while feeding, ophthalmological, musculoskeletal and neuroimaging findings were recorded in subsets of the cohort. Clinical investigations were performed as part of routine care and were not uniform across sites. Accordingly, source-dependent assessments including MRI, EEG, EMG/NCS, formal ophthalmology, hearing assessment, systemic imaging, IQ/DQ testing, MRC scoring and anthropometric Z-scores are reported descriptively or using available-data denominators. Spasticity, hypertonia or possible peripheral nerve involvement was recorded in some clinical summaries; however, electrophysiological confirmation was not uniformly available, and confirmed peripheral neuropathy was not analyzed as a cohort-level prevalence outcome. Functional studies in selected patient-derived cells or model systems demonstrated PI-PLC resistance of GPI-APs, supporting impaired GPI-anchor remodeling. These findings expand the genotypic and recorded phenotypic spectrum of PGAP1 deficiency.

Journal Article↗

PubMed2026

De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.

Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in gene regulation in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 16 de novo pathogenic variants in PCBP1 across 17 subjects from 16 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum disorder (ASD) as a prominent feature. Functional analysis in primary hippocampal mouse neuron cultures indicated that PCBP1 variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subject-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the contribution of PCBP1 in neurogenesis and neuritogenesis, which is impacted by loss-of-function variants expressed in neuronal cells, thereby supporting the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the prominent role of PCBP1 in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.

Journal Article↗

PubMed2026

Biallelic RDH11 variants cause syndromic retinitis pigmentosa with early-onset cataracts and neurodevelopmental delay: a multicenter case series.

Biallelic variants in the RDH11 gene, a retinol dehydrogenase involved in the visual cycle and systemic retinoid homeostasis, were initially implicated in a rare condition characterized by retinal dystrophy, early-onset cataract, neurodevelopmental anomalies and myopathy, through single-family reports, with this association more recently being confirmed in a larger study. Here, we further establish the pathogenic role of RDH11 by presenting a large multi-center cohort, comprising eight individuals from seven unrelated families. Comprehensive genetic analysis identified homozygous variants in all affected subjects, including two novel variants, strongly supporting loss-of-function as the primary disease mechanism. Detailed clinical phenotyping defined a consistent and severe multisystem disorder. Ophthalmologically, the hallmark features include bilateral congenital or early-childhood cataracts requiring surgical intervention, accompanied by retinitis pigmentosa (RP). In terms of extra-ocular involvement, the cohort exhibited a high prevalence of neurodevelopmental delay, including intellectual disability, autistic spectrum disorder and learning difficulties. These features were frequently accompanied by congenital microcephaly, intrauterine and postnatal growth restriction, facial dysmorphisms, and dental anomalies. By significantly expanding both the mutational and phenotypic spectrum of RDH11-related disease, our findings provide independent replication of this gene-disease association and definitively support RDH11 as a bona fide syndromic RP gene.

Journal Article↗

PubMed2026

Optical genome mapping improves structural variant detection and characterization in syndromic and neurogenetic disorders.

Optical Genome Mapping (OGM) offers superior resolution compared to standard diagnostic methods such as karyotyping and FISH, enabling the detection of nearly all types of chromosomal aberrations with non-centromeric breakpoints. This study evaluated OGM's potential to enhance the genetic findings in unsolved cases of neurogenetic and syndromic disease requiring further investigation after standard genetic testing. In 10 patients with various neurogenetic diagnoses, OGM confirmed all structural findings previously detected by karyotyping, chromosomal microarray (CMA), and/or NGS. Moreover, OGM provided additional structural insights in five cases, such as identifying a novel candidate gene in a patient with a balanced translocation, redefining of breakpoint regions in familial translocations, characterization of complex rearrangements, and revising of initial diagnostic interpretations. Most importantly, we present OGM results for three individuals with ring chromosomes 18, 20, and 22, highlighting the need to adjust filter settings and to incorporate the rare variant pipeline for accurate detection. Based on our experiences, we propose a strategic approach for identifying ring chromosomes using OGM. On the other hand, OGM did not identify causative variants in three unsolved cases with strong clinical suspicion of hereditary neuropathy. In summary, while OGM did not yield new insights for hereditary neuropathy, it provided additional or refined information in 6 out of 10 cases with other syndromic diseases. These findings underscore the value of OGM in increasing the diagnostic yield and precision of genetic testing.

Humans↗