Uğur Gümüş

Background: In males, MECP2 loss of function was long thought to be lethal or uniformly severe, and affected boys remain under-recognised. Their clinical range is still poorly defined. Methods: We assembled a multicentre Turkish series of 22 hemizygous male probands ascertained through routine diagnostic testing rather than severe-phenotype registries. Variants were classified under the ClinGen Expert Panel specification for MECP2 (GN036, version 6.0.0) and its combining rules, with the Panel’s ClinVar classifications adopted where available. Phenotypic analysis was restricted to the 21 probands with pathogenic, likely pathogenic or uncertain variants. Results: The 22 probands carried 17 distinct variants (11 missense, 5 frameshift and one 3’ untranslated region deletion), of which 2 were classified as pathogenic, 1 likely pathogenic, 13 uncertain and 1 benign (3, 4, 14 and 1 probands, respectively). Where recorded, intellectual disability or developmental delay affected 7 of 7 probands with pathogenic or likely pathogenic variants and 8 of 10 with uncertain variants; seizures affected 2 of 3 and 8 of 10, respectively. Growth or head-circumference findings, recorded in 9 of 21 probands, included obesity or overgrowth (5), microcephaly (4, one borderline) and short stature (3). A maternal carrier was identified in 6 of 22 families (five laboratory-confirmed); the other 16 mothers were untested, so no de novo event was confirmed. Second-locus findings, reported by referring laboratories in 3 probands, could not be independently reclassified. Conclusions: In this diagnostically ascertained series, phenotypes observed among males carrying MECP2 variants were graded rather than uniformly severe. Fourteen of the 21 probands carry variants of uncertain significance, in whom causation is not established, so the range that may be attributed to MECP2 rests on seven individuals carrying variants classified as pathogenic or likely pathogenic under the stated criteria. In one of them, published functional data on the identical variant conflict with its pathogenic classification, so attribution of his phenotype to MECP2 remains uncertain. These provisional observations support a low threshold for MECP2 testing in males with unexplained neurodevelopmental presentations, attention to growth as well as head circumference, and consideration of additional loci.

Background: Osteopetrosis (OP) is a rare, severe inherited disorder of bone metabolism caused by impaired osteoclast function. The most severe form, malignant infantile osteopetrosis (MIOP), presents in early life with bone abnormalities, neurologic issues, and often hypocalcemia and carries a high mortality rate if left untreated. This study aimed to define the molecular spectrum and delineate genotype-phenotype correlations in a cohort of patients from a single pediatric hematology center. Methods: We retrospectively reviewed the medical, laboratory, radiological, and genetic data of 12 children with OP followed between 2012 and 2022. Whole-exome sequencing was used for genetic analysis. Results: The median age at diagnosis was three months. The most frequently mutated gene was TCIRG1 (n=7, 58.3%), followed by OSTM1 (n=3, 25%), and CLCN7 (n=2, 16.7%). A novel homozygous deletion in TCIRG1 was identified. A strong genotype-phenotype correlation was observed. Patients with TCIRG1 mutations predominantly presented with severe bone marrow failure and osteopetrorickets. In contrast, all patients with OSTM1 and CLCN7 mutations exhibited significant neurodegenerative changes. Two patients received hematopoietic stem cell transplantation (HSCT), with one survivor. Conclusion: This study highlights the distinct clinical and genetic heterogeneity of MIOP. Our findings reinforce that the specific genetic mutation is critical for predicting the disease course—hematological complications for TCIRG1 versus primary neurodegeneration for OSTM1 and CLCN7. This genetic diagnosis is essential for counseling families and determining eligibility for curative therapies like HSCT.

The concept of ‘developmental and epileptic encephalopathy (DEE)’ recognises that in infants presenting with severe early-onset epilepsy, neurodevelopmental comorbidity may be attributable to both the underlying cause and to adverse effects of uncontrolled epileptic activity. There is no direct genotype – phenotype correlation in DEEs. This study aimed to report the genetic and phenotypic differences in patients with DEE. Genetic evaluations of the patients were performed due to epilepsy combined with developmental delay, epileptic encephalopathy, motor deficits, autistic features, or cognitive impairment. Patients were assessed for demographic characteristics, medical history, family history, psychomotor development, seizure control interventions, electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings. This study included 20 children aged 0–16 years who were diagnosed as having DEE.The types of DEE detected in our study were DEE 2, 4, 6B, 7, 11, 26, 30, 33, 35, 42, 58, 62, and 67.Status epilepticus was recorded in only DEE7. The most common EEG abnormality was multifocal epileptic discharges (35%,) followed by burst-suppression patterns in patients with neonatal-onset seizures. Thirteen of the children were aged over 2 years, two (15%) were non-ambulatory and six (46%) were non-verbal. MRI scans were normal in 80% of the patients. Refractory epilepsy seen in 33% of cases.De-novo mutation, microcephaly and dysmorphic findings accompany resistant seizures and are associated with poor prognosis For patients with movement disorders, developmental delay, autism, and ID with or without epilepsy in any period of their life, next-generation sequencing is the only diagnostic technique available, with genetic analysis often being the only diagnostic method.