Turkan Turkut Tan

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.

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.

KBG syndrome is a rare autosomal dominant disorder caused by ANKRD11 variants, characterized by distinctive craniofacial features, short stature, skeletal anomalies, and neurodevelopmental impairment. Regional studies, particularly from underrepresented populations, are essential to broaden the clinical and molecular spectrum of the syndrome. We retrospectively analyzed the clinical, molecular, and anthropometric data of 23 Turkish individuals with molecularly confirmed KBG syndrome. Molecular analyses included whole exome sequencing, clinical exome sequencing, and targeted gene panels. Variants were classified according to ACMG guidelines, and phenotypic features were systematically assessed using standardized criteria. Eighteen distinct ANKRD11 pathogenic or likely pathogenic variants were identified, including eight novel variants, predominantly located in exon 9. Short stature (height SDS < –2) was documented in 30.4% of patients. Intellectual disability was observed in 82.6%, and behavioral anomalies in 52.2% of the cohort. Craniofacial dysmorphism, including long philtrum, triangular facial shape, and macrodontia, was prominent. No genotype–phenotype correlation could be established. This study expands the mutational landscape of ANKRD11 and underscores the clinical variability of KBG syndrome in a Turkish cohort. Our findings emphasize the importance of integrating molecular and detailed clinical evaluations for early diagnosis, especially in diverse populations with limited prior representation.

Diagnostic Utility in Next-Generation Sequencing by Implicating CNV Analysis in Eleven Patients with Peters Plus Syndrome: A Single-Center Experience - Journal of Clinical Research in Pediatric Endocrinology

Aagenaes syndrome, also known as lymphoedema cholestasis syndrome 1 (LCS1), is a rare autosomal recessive disorder characterized by neonatal cholestasis and chronic lymphedema, primarily affecting the lower extremities. The genetic basis for this syndrome was recently linked to a variant in the 5′‐untranslated region (5’‐UTR) of the UNC45A gene, located on chromosome 15q. This study aimed to identify the genetic mutations associated with Aagenaes syndrome in two siblings and to explore their clinical implications. Whole‐exome sequencing (WES) was conducted on two siblings with neonatal cholestasis and lymphedema. WES identified a single base pair change in the 5′‐untranslated region (5’‐UTR) of the UNC45A gene (c.‐88G>A) in both siblings. Additionally, both were heterozygous for an exonic loss‐of‐function variant (c.1591C>T; p.Arg531Ter) in UNC45A. Clinically, both siblings presented with neonatal cholestasis and lymphedema; however, one sibling developed severe liver failure, requiring a liver transplant. Despite carrying the same variants, the clinical outcomes differed between the two patients. The identification of a novel 5’‐UTR variant (c.‐88G>A), along with an exonic variant in UNC45A, expands the genetic and clinical understanding of Aagenaes syndrome. This study confirms the involvement of the 5’‐UTR region of UNC45A in the disease pathogenesis, while demonstrating that Aagenaes syndrome is not exclusively associated with the previously reported c.‐98G>T variant found in Norwegian cases. These findings underscore the importance of genetic screening for accurate diagnosis and management of Aagenaes syndrome and provide new insights into the critical regulatory role of the 5’‐UTR in disease development. Further research is needed to elucidate the mechanisms underlying phenotypic variability in this rare disorder. Evaluation of mRNA and protein levels would have been valuable to better understand the functional effects of these variants; however, due to current resource constraints, such studies could not be conducted.

Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB) is a rare neuroectodermal syndrome caused by somatic mosaic mutations in the RHOA gene. It presents with linear skin hypopigmentation, facial and limb asymmetry, dental and acral anomalies, and leukoencephalopathy, generally preserving intellectual and neurological functions. We report two cases of EDFAOB. Both cases initially presented with notable facial‐body asymmetry, thin hair, dental issues, digital anomalies, and Blaschko's lines‐aligned hypopigmentation. A 6‐year‐old girl exhibited esotropia, visual center atrophy, and bilateral white matter hyperintensities on MRI. A 10‐year‐old girl had unilateral hyperintense lesions in the left cerebral hemisphere on MRI. Both had normal neuromotor development without intellectual impairment. RHOA gene sequencing from hypopigmented skin biopsies revealed the c.139G > A (p.Glu47Lys) mutation, with allele fractions of 20% and 10%, respectively, absent in blood leukocytes and parental DNA. These cases highlight the clinical and genetic features of EDFAOB and underscore the importance of thorough clinical evaluation to guide precise genetic testing. The identification of mutations exclusively in affected tissues supports a postzygotic mosaic distribution, refining the diagnostic approach for this syndrome.