Tahir Atik

Sotos syndrome is an overgrowth disorder caused by heterozygous NSD1 variants, partial‐gene deletions, or 5q35 microdeletions. Malan syndrome, a phenotypically overlapping condition, results from haploinsufficiency of the NFIX gene due to either heterozygous chromosomal microdeletions involving the 19p13.2 region or heterozygous loss‐of‐function variants. This multicenter study aimed to characterize the clinical and molecular features of individuals with Sotos and Malan syndromes in Türkiye. We retrospectively analyzed clinical and molecular data from 48 individuals with genetically confirmed Sotos or Malan syndrome across 14 centers. Molecular analyses included whole‐exome sequencing, clinical exome sequencing, targeted gene panels, multiplex ligation–dependent probe amplification, and chromosomal microarray analysis. Forty‐two individuals were diagnosed with Sotos syndrome and six with Malan syndrome. All exhibited characteristic facial features, and 97.9% had developmental delay or intellectual disability. We identified a total of 38 NSD1 variants, of which 35 were classified as pathogenic or likely pathogenic and three as variants of uncertain significance; notably, 23 of these variants were novel. Three patients carried 5q35 microdeletions, and one had an intragenic deletion involving exons 10–11. Four distinct NFIX variants (two novel) were detected in five patients, and one carried a 19p13.13 deletion encompassing the entire gene. This nationwide study expands the genotype–phenotype spectrum of Sotos and Malan syndromes in Türkiye and supports improved diagnostic and clinical management strategies.

Xia–Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by heterozygous variants in the AHDC1 gene. While the core phenotype includes developmental delay, hypotonia, and expressive language impairment, the syndrome displays considerable clinical and genetic heterogeneity. Data from non‐European populations remain scarce. We report the clinical and molecular findings of five unrelated Turkish patients with XGS diagnosed via whole‐exome sequencing (WES). This is a multicenter study, and clinical data were collected from participating centers using standardized forms. All patients carried heterozygous, de novo AHDC1 variants (three frameshift, two nonsense), all of which were classified as pathogenic or likely pathogenic. Three of these, p.(Ala1432Profs13), p.(Val900Glyfs2), and p.(Val704Profs*26), are novel and predicted to cause protein truncation. Nonsense mutations are p.(Arg108*) and p.(Trp638*), which were previously reported as disease‐causing. One patient had dual diagnoses with AHDC1 and CDK13 variants, explaining ocular and cardiac anomalies, leading to a particularly severe neurodevelopmental phenotype. This is the largest study reported to date in Turkey on XGS, a rare genetic disorder, further expanding the disease's genotypic and phenotypic spectrum. Recognition of dual diagnoses in a single patient underscores the value of WES in detecting complex genotypes and avoiding misattributed genotype–phenotype associations. As a recently described syndrome, careful evaluation of patients with XGS for atypical phenotypes may provide important contributions to the clinical presentation described in the literature.

Background: Optical genome mapping (OGM) is a novel technology that enables high-resolution detection of structural variants. This study aimed to evaluate the diagnostic contribution of OGM in early-onset developmental epileptic encephalopathies (DEEs) with unresolved genetic causes. Materials and methods: A total of 38 children with early-onset DEEs (aged 0–18 years) who remained undiagnosed despite conventional karyotyping, chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) were included. All patients underwent detailed phenotypic reassessment and WES reanalysis. One patient received a definitive molecular diagnosis following WES reanalysis. Four patients subsequently withdrew consent, and one patient was excluded due to inadequate DNA quality for OGM. OGM was therefore performed in the remaining 32 patients. Potential OGM findings were validated using appropriate laboratory techniques. Results: Among the 32 patients who underwent OGM, three candidate structural variants were identified. Two variants (2/32, 6.3%), ogm[GRCh38] ins(X;?)(q27.3;?) and ogm[GRCh38] 6p24.1 (13083829_13279761)x1, were confirmed using orthogonal validation methods, resulting in the molecular diagnoses of Fragile X syndrome and PHACTR1- related DEE, respectively. Conclusion: OGM contributed to the identification of clinically relevant structural variants in genetically undiagnosed early-onset DEEs. These findings support the complementary role of OGM in the genetic evaluation of complex neurodevelopmental disorders.

Background: The disruption of neural progenitor proliferation is a key mechanism underlying primary microcephaly, yet how cell cycle arrest leads to progenitor loss remains only partially understood. Cyclin-dependent kinases, CDK4 and CDK6, are central regulators of the G₁/S transition, but their role in cellular stress responses during neurodevelopment remains unclear. Methods: We studied fibroblasts from affected individuals in two families: siblings homozygous for a CDK4 frameshift (p.Glu94Argfs*65) presenting with microcephaly and pontine hypoplasia and a child homozygous for a CDK6 missense variant (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Results: Loss-of-function variants in CDK4 and CDK6 , core G₁/S regulators, impaired proliferation and induced mitochondrial stress responses and apoptosis. Mutant fibroblasts exhibited significantly reduced DNA synthesis and cell cycle progression, along with increased mitochondrial activity, elevated reactive oxygen species and increased apoptosis. Mitochondrial responses differed by gene: CDK4 deficiency caused mitochondrial hyperpolarisation, while CDK6 deficiency resulted in depolarisation, suggesting differences in mitochondrial apoptotic dynamics. Both variants affected mTOR pathway signalling, linking cell cycle kinase loss to disrupted metabolic regulation. Conclusion: These findings uncover a previously unrecognised mitochondrial stress response accompanying proliferative failure, offering mechanistic insight into how cell cycle arrest could lead to neural progenitor depletion and brain growth disorders. More broadly, our results connect cyclin-dependent kinase dysfunction with mitochondrial homeostasis in neurodevelopment, highlighting shared pathways with neurodegeneration and cancer.

Background: GNE mutations are rare pathologic conditions that can cause severe thrombocytopenia and bleeding tendency from the neonatal period. The clinical presentation of patients with GNE mutations varies from mild skin and mucosal bleeding to life-threatening bleeding. Case Presentation: This study reported two siblings with hereditary thrombocytopenia. The 2 patients exhibited severe thrombocytopenia (platelet [PLT] count: A [p.Gly559Arg]) was detected in GNE . One sibling was unresponsive to the platelet receptor agonists eltrombopag and romiplostim. Meanwhile, the other sibling was unresponsive to eltrombopag but was responsive to romiplostim. Conclusion: The first-line treatment of patients with GNE mutations is PLT transfusion. However, the management of patients with severe thrombocytopenia and frequent bleeding is challenging. Thrombopoietin receptor agonists are administered to these patients to mitigate the risk of alloimmunization and PLT transfusion refractoriness. However, the observed responses may differ even in siblings carrying the same mutation. This differential response may be related to bone marrow megakaryocyte reserves and hepatocyte Aswell-Morell receptor levels.

Objectives: Mucolipidosis (ML) type II α/β (I-cell disease) and type III (Pseudo-Hurler polydystrophy) are rare autosomal recessive lysosomal storage disorders caused by mutations in the GNPTAB (ML III α/β) and GNPTG (ML III γ) genes, leading to impaired lysosomal enzyme trafficking. These disorders manifest as progressive multisystem diseases with skeletal, neurological, cardiovascular, and respiratory involvement. This study aims to characterise pediatric patients’ clinical, biochemical, genetic, and radiological findings with ML II α/β and IIIα/β or γ to enhance understanding of disease diagnosis and progression. Methods: This retrospective cohort study included 19 pediatric patients (15 ML II α/β, 3 ML III γ, 1 ML III α/β) diagnosed at a tertiary referral center. Clinical data, including facial dysmorphism, skeletal abnormalities, organomegaly, cardiovascular involvement, and neurological findings, were recorded at baseline and follow-up. Biochemical analysis included urinary glycosaminoglycan (GAG) levels and lysosomal enzyme activities. For molecular diagnostics, next-generation sequencing (NGS) was utilized using a targeted gene panel that contained GNPTG and GNPTAB leukocytes from peripheral blood were used to harvest genomic DNA. Following the 2015 ACMG/AMP standards, variant interpretation was carried out by evaluating pathogenicity using in silico prediction methods, population frequency data, and segregation analysis. Radiological findings were evaluated via skeletal X-rays and brain MRI. Results: The median age at diagnosis was 8 months (range: 1 day–252 months), with a consanguinity rate of 63.1 %. ML II α/β patients presented earlier and had more severe findings, including coarse facies, respiratory tract involvement, cardiac abnormalities, and joint contractures. Cardiac valve disease, kyphosis, and progressive hearing loss were frequent. The most common mutation in GNPTAB was c.3503_3504delTC in ML II α/β, while GNPTG variants were linked to ML III γ. Radiologic findings often included hip dysplasia; brain MRIs showed callosal and subarachnoid abnormalities in a few cases. Median survival in ML II α/β was 28 months, mainly due to respiratory failure. Enzyme assays revealed elevated β-hexosaminidase A and A+B, α-D-mannosidase, and α-L-fucosidase activities in both leukocyte and DBS samples, consistent with molecular diagnoses. Conclusions: In addition to reporting six novel GNPTAB/GNPTG mutations, this study highlights the diagnostic potential of dried blood spot (DBS) samples, where elevated lysosomal enzyme activity may offer a valuable, minimally invasive screening method for ML II/III.

Genetic factors contributing to hearing loss (HL) are heterogeneous, and effective medical treatments remain limited. We identified 3 distinct missense variants in CPD , encoding carboxypeptidase D, in 5 individuals with congenital deafness from 3 unrelated families, affecting the catalytically active CP domain 2 of this protein. Subsequent analysis of a larger cohort from the 100,000 Genomes Project revealed an enrichment of rare protein-altering CPD variants in individuals with HL. We show that CPD localizes to sensory epithelium and nerve cells in the mouse cochlea, and the enzymatic activity of CPD, crucial for nitric oxide (NO) production through arginine processing, is impaired in affected individuals. The levels of arginine, NO, and cGMP in patient-derived fibroblasts are also decreased, leading to endoplasmic reticulum stress–mediated responses being triggered in the cells. Silencing of Cpd in organotypic mouse cochlea cultures leads to increased apoptosis. Finally, Drosophila models of CPD deficiency display defective Johnston’s organ, impaired auditory transduction, and sensory and movement abnormalities. Notably, these phenotypes are partially rescued by supplementation with arginine or sildenafil, a cGMP enhancer. Our findings establish CPD mutations as a cause of congenital HL, highlighting that the NO signaling pathway offers a promising therapeutic avenue.