Parkinsonism Relat Disord. 2026 May 22;148:108367. doi: 10.1016/j.parkreldis.2026.108367. Online ahead of print. ABSTRACT BACKGROUND: While genetic testing in Movement Disorders (MD) has expanded enormously, access to genetic testing and genetic counseling remains asymmetric at the global scale. Guidance on efficient testing strategies for clinicians, governments and stakeholders is crucial. OBJECTIVES: Establish a list of genetic movement disorders considered essential as determined by a group of MD experts. METHODS: All genes associated with MD were searched using the OMIM and MDS Gene database. We collected all additional tests available at 4 different laboratories from the EuroGentest database. The results were compiled in 6 questionnaires. A genetic test was considered essential if molecular testing had a direct impact in the management of the patient, including treatment of the disease or its comorbidities, or genetic counseling of the patient and family members. Two Delphi rounds were conducted asking MD experts which specific tests they considered essential in an adult MD clinic. RESULTS: Fifty-nine disorders were considered essential to genetically identify by the MD experts. This included 25 genes associated with ataxia, 15 with parkinsonism, 14 with dystonia, eight with chorea, five with paroxysmal disorders, four with myoclonus, four with hereditary spastic paraparesis, and one with tremor. Sixteen disorders reached 100% consensus among experts: Huntington’s disease, PxMD-PPRT2, Wilson’s disease, DYT-SGCE, DYT-THAP1, DYT-TOR1A, DYT/PARK-GCH1, Fragile-X Tremor-ataxia syndrome, PARK-GBA, PARK-LRRK2, PARK-PINK1, PARK-PRKN, PARK-SNCA, Cerebrotendinous Xanthomatosis, Ataxia-Telangiectasia, and Niemann-Pick disease type C. CONCLUSION: This study provides a list of genetic MD that should be molecularly tested in adult centers with a compatible phenotype according to a group of MD experts. PMID:42202611 | DOI:10.1016/j.parkreldis.2026.108367

Am J Med Genet A. 2025 Nov 26:e70007. doi: 10.1002/ajmga.70007. Online ahead of print. ABSTRACT SLC30A9 mutations are linked to Birk-Landau-Perez syndrome, which is characterized by neurodevelopmental and renal disease, thought to result from impaired zinc homeostasis. In this report, we describe a patient with a homozygous likely pathogenic SLC30A9 variant with atypical chorio-retinal degeneration, suggesting retinal involvement in SLC30A9-associated diseases. The patient has bilateral sensorineural hearing loss, developmental delay, intellectual disability, abnormal balance, and Tourette syndrome. Ophthalmic manifestations include vascular attenuation, optic disc pallor, and pigmentation. In addition, the patient is noted to have high myopia. Our case highlights the importance of broad genetic testing in diagnosing rare multi-systemic disorders. Further research into the molecular mechanisms by which SLC30A9 results in photoreceptor disease is essential to understand its role in retinal degeneration and to develop potential therapeutic strategies. PMID:41293997 | DOI:10.1002/ajmga.70007

Cell Stem Cell. 2025 Nov 3:S1934-5909(25)00374-1. doi: 10.1016/j.stem.2025.10.006. Online ahead of print. ABSTRACT Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches. PMID:41187745 | DOI:10.1016/j.stem.2025.10.006

HGG Adv. 2025 Oct 25:100539. doi: 10.1016/j.xhgg.2025.100539. Online ahead of print. ABSTRACT Human development is a complex process that requires precise control of gene expression through regulatory proteins. Recently, heterozygous variants in PRR12, encoding a proline-rich regulatory protein, were found to cause a variable phenotype involving developmental delay/cognitive impairment, neuropsychiatric diagnoses, structural eye anomalies, congenital heart and kidney defects, and poor growth. QSER1, encoding glutamine- and serine-rich protein 1, represents a paralog of PRR12 that shares 28% overall identity at the protein level and stronger conservation (43%) in the C-terminal region. QSER1 deficiency in human embryonic stem cells causes hypermethylation of many key transcription factor genes, implicating it in the development of multiple organs. Here we present three unrelated individuals with neurodevelopmental phenotypes, variable other multisystem anomalies, and heterozygous variants in QSER1. This includes two novel de novo frameshift alleles (p.(Lys1565Argfs*36) and p.(Phe896fs*28)), and one ultra-rare canonical splice site variant resulting in a combination of abnormal transcripts, frameshift (p.(Glu1393Glyfs*26)) and in-frame deletion of a conserved amino acid (p.(Glu1393del)), supported by in silico predictions and minigene assays. In situ hybridization revealed dynamic and broad expression of qser1 in zebrafish embryos, including a strong presence in the developing brain. These data suggest a possible role for QSER1/qser1 in vertebrate development and human disease. PMID:41139957 | DOI:10.1016/j.xhgg.2025.100539

J Med Genet. 2025 Oct 8:jmg-2025-110631. doi: 10.1136/jmg-2025-110631. Online ahead of print. ABSTRACT BACKGROUND: Pathogenic gain-of-function or dominant-negative effect missense variations in ACTB are associated with a neurodevelopmental disorder characterised by intellectual disability (ID), seizures, sensorineural hearing loss, cerebral, renal and ocular abnormalities and dysmorphic features (Baraitser-Winter cerebrofrontofacial syndrome). ACTB encodes beta-actin, a highly conserved protein involved in cell motility, structure and integrity. Deletions including ACTB, and, more rarely, single-nucleotide loss-of-function variants in ACTB have been described in patients with a distinct phenotype including developmental delay, ID, microcephaly, growth restriction, cardiac and renal abnormalities and dysmorphic features. METHODS: We collected 14 individuals and 1 fetus carrying a heterozygous deletion including ACTB, and 4 individuals with a heterozygous truncating variant. Genotypic and phenotypic data were analysed. Furthermore, a comprehensive review of all cases reported to date was also undertaken. RESULTS: Twelve out of 17 individuals presented with ID, and 3 out of 17 with learning disabilities. Speech delay and behavioural abnormalities were observed in 15 out of 17 and 12 out of 17 individuals, respectively, motor delay in 9 out of 17 and growth restriction in 9 out of 18. Most of the individuals (13/18) had recognisable dysmorphic features. 11 anomalies were de novo, except for 1 deletion inherited from the mother. The size of the deletion varied from 125 kb to 1.6 Mb and could result from a fork stalling and template switching. CONCLUSION: This study allowed us to better characterise the phenotype associated with the haploinsufficiency of ACTB, underlying the high prevalence of neurodevelopmental disorders (ID, speech and motor delay, behavioural abnormalities) and growth restriction in this recognisable syndrome. PMID:41062261 | DOI:10.1136/jmg-2025-110631