Kadri Karaer

Objective: To evaluate the diagnostic utility and genetic spectrum of next‐generation sequencing (NGS) in a large, well‐phenotyped cohort of Turkish pediatric patients with epilepsy of unknown etiology. Methods: Between January 2021 and December 2024, 250 children (115 female, 135 male) with unexplained epilepsy underwent either whole‐exome sequencing (WES; n = 104) or clinical exome sequencing (CES; n = 146). Variants were interpreted according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical data, including seizure semiology, neuroimaging, EEG findings, and treatment response, were retrospectively reviewed. Results: A definitive molecular diagnosis (pathogenic or likely pathogenic variants) was established in 89 patients (89/250, 35.6%). Including variants of uncertain significance (VUS) with strong phenotypic correlation raised the diagnostic yield to 57.6% (144/250). The genetic landscape was highly heterogeneous, involving 59 distinct genes. SCN1A was the most frequently implicated gene ( n = 11, 12.4% of diagnosed cases), followed by MECP2 and PRRT2 ( n = 5 each). Notably, the recurrent PRRT2 c.649dup (p.Arg217Profs*8) frameshift variant was identified in four unrelated Turkish families. Inheritance patterns included autosomal dominant (56/89, 63%), autosomal recessive (20/89, 22%), and X‐linked (13/89, 15%). Diagnostic yields were comparable between WES (38/104, 36.5%) and CES (51/146, 35%) ( p = 0.97). Neonatal‐onset epilepsy ( p = 0.03) and the presence of autistic features ( p = 0.04) were significantly associated with a positive genetic diagnosis. Conclusion: Our study confirms NGS as a first‐tier diagnostic tool in pediatric epilepsy, revealing a distinctive genetic architecture enriched with novel and population‐specific variants. These findings emphasize (1) a high diagnostic yield (∼36%) supporting first‐tier use of NGS; (2) a distinctive genetic architecture characterized by recurrent PRRT2 variants and an elevated burden of autosomal recessive disorders, likely reflecting regional consanguinity patterns; and (3) a phenotype‐driven framework for prioritizing VUS re‐evaluation in clinical neurology practice. Such data from underrepresented populations are crucial for global genomic databases and directly inform precision medicine and genetic counseling.

Pathogenic variants in kinesin KIF11 underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association of KIF11 (encoding EG5) with development of the lymphatic system and how KIF11 pathogenic variants lead to lymphatic dysfunction and lymphedema remain unknown. Using patient-derived lymphoblastoid cells, we demonstrated that patients with MLC carrying pathogenic stop-gain variants in KIF11 have reduced mRNA and protein levels. Lymphoscintigraphy showed reduced tracer absorption, and intestinal lymphangiectasia was detected in one patient, pointing to impairment of lymphatic function caused by KIF11 haploinsufficiency. We revealed that KIF11 is expressed in early human and mouse development with the lymphatic markers VEGFR3, podoplanin, and PROX1. In zebrafish, single-cell RNA-Seq identified kif11 specifically expressed in endothelial precursors. In human lymphatic endothelial cells, EG5 inhibition with ispinesib reduced VEGFC-driven AKT phosphorylation, migration, and spheroid sprouting. KIF11 knockdown reduced PROX1 and VEGFR3 expression, providing for the first time to our knowledge a link between KIF11 and drivers of lymphangiogenesis and lymphatic identity.

Background . This study aims to characterize the clinical phenotype of a family with two siblings exhibiting neurological manifestations, utilizing whole exome sequencing (WES) to identify potential pathogenic variants within the NRXN2 gene. Methods . A consanguineous family with two affected siblings displaying developmental delay, severe intellectual disability, epilepsy, and speech delay was examined. WES was performed on DNA samples from affected and unaffected family members, followed by a comprehensive bioinformatics analysis. In-silico tools were employed for variant interpretation and structural modeling of the NRXN2 protein. Clinical and genetic data were integrated to elucidate the potential impact of the identified variant. Results . WES revealed a novel homozygous missense variant (c.1475T>G, p.Leu492Arg) in the NRXN2 gene in both affected siblings. This variant was absent in healthy family members and public databases. In-silico analysis predicted a detrimental effect on protein function. Parental segregation confirmed heterozygous carrier status. The variant was classified as ‘Likely Pathogenic’ based on ACMG/AMP criteria. Conclusion . This study identifies a novel homozygous missense variant in NRXN2 associated with global developmental delay, severe intellectual disability, speech delay and epilepsy. The findings underscore the critical role of NRXN2 in neurodevelopment and highlight the potential implications of genetic variations within this gene in neurodevelopmental disorders. Further research and functional validation are warranted to deepen our understanding of NRXN2 -related disorders and explore potential therapeutic interventions.

We present two novel mutations of RPS6KA3 in two Turkish boys with CLS. As reported in previous publications, growth and developmental delay and phenotypic appearance were typical in our cases.

Introduction: Pallister-Hall-Like Syndrome (PHLS) (OMIM #241800), a rare ciliopathy associated with defects in the Sonic Hedgehog pathway, is characterized by postaxial polydactyly, hypothalamic hamartoma, cardiac and skeletal anomalies, and craniofacial dysmorphisms. Case Report: This report describes a 3-day-old girl from a consanguineous family diagnosed with bilateral postaxial polydactyly and facial dysmorphism. Genetic analysis revealed a homozygous pathogenic c.1726 C>T; p.Arg576Trp variant in the SMO gene. Conclusion: Consanguineous marriage causes predisposition to ultra-rare conditions. There have been eleven documented cases of this ultra-rare syndrome. To our knowledge, this is the first reported case in Turkiye, enriching our clinical understanding of PHLS.

Purpose: RASopathies encompass a spectrum of disorders resulting from pathogenic variants in genes associated with the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway, critical for cellular functions like proliferation, differentiation and survival. Noonan syndrome (NS), the most prevalent form of RASopathies, presents with a myriad of clinical features including characteristic facial dysmorphisms, congenital heart defects, and developmental delays. Despite its clinical recognition, molecular confirmation remains elusive in a notable percentage of cases. In this study, we aimed to investigate the clinical and molecular profiles of six patients diagnosed with NS, focusing on the role of PTPN11 gene mutations. Materials and methods: Molecular evaluation was performed using PTPN11 gene sequence analysis and whole gene sequencing methods in six patients who were thought to have typical NS phenotypes based on clinical evaluations. Results: Molecular screening in patients identified four different pathogenic variants in the PTPN11 gene. These variants, all heterozygous, were classified as pathogenic according to established criteria. Conclusion: Our findings contribute to understanding the genetic landscape of NS and underscore the significance of molecular analysis in confirming diagnoses.

Purpose: Familial Mediterranean Fever (FMF) is a hereditary auto inflammatory disease (MIM#249100). The most common symptoms are high fever, abdominal pain and arthralgia. FMF is the result of variations in the MEditerraneanFeVer (MEFV) gene, which is located on chromosome 16p13.3, consists of 10 exons and encodes the pyrin (marenostrin) protein. The frequency of MEFV gene variants that cause FMF varies according to ethnic groups, countries and even different regions in the same country. In this study, we aimed to determine the frequency and distribution of MEFV gene alterations that cause Familial Mediterranean fever in southeastern Turkey. Materials and Methods: A total of 6,660 patients with a prediagnosis of FMF, including 3,495 women and 3,165 men, were included in the study. Fragment analysis was performed to investigate the MEFV gene variations of the patients and the 19 most common variants in the Turkish population were examined. Results: We found at least one variation in 50.17% (3,341) of our 6,660 patients. In our patients, 108 different genotypes; in Exon 2, 3, 5 and 10 and we identified 16 different variations. We found 2,120 (63.21%) patients heterozygous, 693 (20.74%) compound heterozygotes, 275 (8.23%) homozygous and 261 (7.81%) complex genotypes. The 5 variants with the highest allele frequency are respectively; R202Q (27.84%), M694V (22.83%), E148Q (21.98%), V726A (7.42%), and M680I(G>C) (6.39%). Conclusion: We identified the most common prevalence of MEFV gene alteration in a large patient group in our region. High R202Q mutation rates were among the remarkable results of this study.

Neurodevelopmental disorder with microcephaly, ataxia, and seizures (NEDMAS) syndrome is a rare neurodevelopmental disorder characterized by moderate intellectual disability (ID), thin body habitus, microcephaly, seizures, ataxia, muscle weakness, and speech impairment. So far, only two families with NEDMAS have been reported. We report the clinical and molecular characteristics of three unrelated Turkish families with four NEDMAS patients. Whole-exome sequencing was used to search for the disease-causing variant. The main manifestations of the probands are severe developmental delay and ID, thin body habitus, and severe hypotonia. Brain imaging revealed bilateral cerebral and cerebellar diffuse atrophy. Sequencing results showed that both patients carried a novel missense variant c.1196C>T (p.Thr399Met) in the seryl-tRNA synthetase gene. Our findings help expand the variant spectrum of NEDMAS and provide additional information for diagnosing cases with atypical features.