Adife Gulhan Ercan‐Sencicek

Gliomas with mutant isocitrate dehydrogenase (IDH) are malignant brain tumours that typically arise in early to mid-adulthood and nearly always recur following treatment ^1,2 . However, the genetic and cellular-state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA and RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumour types. We show that malignant cell states transcriptionally resemble stages of normal glial–neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH wild-type glioblastoma ^3,4 . Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell-state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were enriched in gliomas that acquired recurrence-associated genetic events. These included treatment-associated hypermutation, increased copy number changes and cell cycle alterations. Second, increased mesenchymal-like-state abundance occurred independently of acquired genetic alterations and instead coincided with elevated macrophage expression. Overall, our findings provide an integrative model that traces the cell intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.

Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions¹. Lissencephaly (‘smooth brain’) spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability². However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller–Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders.

Objective: The study aimed to show the clinical characteristics and prognosis of the L1 syndrome in patients with L1CAM mutations in the extracellular region. Materials and Methods: Three affected boys and their siblings and parents from a large family were included in this study. Genetic etiology was investigated by whole-exome sequencing in the index patient. The pathogenic variant was detected by whole-exome sequencing and was validated by Sanger sequencing in 3 patients and other family members. Results: We present 2 brothers and their cousin with prenatal onset hydrocephalus, severe developmental and speech delay, corpus callosum agenesis/hypogenesis, epilepsia, and adducted thumbs. A hemizygous missense mutation NM_024003 (c.A2351G:p.Y784C) on exon 18 of L1CAM gene was found in the 3 patients and their carrier mother. This missense mutation in the conserved region of the second fibronectin type III-like repeats located in the extracellular region of L1CAM resulted in the severe phenotype of X-linked inherited L1 syndrome in the patients. Conclusion: L1 syndrome should be considered in the differential diagnosis of male children with intellectual disability, hydrocephalus, and adducted thumbs. While truncating mutations of L1CAM may cause a more severe phenotype, missense mutations cause milder forms. However, pathogenic missense mutations affecting key amino acid residues lead to severe phenotype likely Cite this article as: Tüysüz B, Ercan-Şençiçek AG, Özer E, Goc N, Yalçınkaya C, Bilguvar K. Severe phenotype in patients with X-linked hydrocephalus caused by a missense mutation in L1CAM. Turk Arch Pediatr. 2022;57(5):521-525.

Backgrounds: While many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts.Methods: We recruited 73 CHD probands from consanguineous families in Turkey and used whole‐exome sequencing (WES) to identify genetic lesions in these patients.Results: On average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss‐of‐function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D‐TGA). Three additional patients (4.1%) harbored other types of CHD‐associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity.Conclusions: Our WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey.

Background: Phosphatase and tensin homolog (PTEN) germline mutations are associated with cancer syndromes (PTEN hamartoma tumor syndrome; PHTS) and in pediatric patients with autism spectrum disorder (ASD) and macrocephaly. The exact prevalence of PTEN mutations in patients with ASD and macrocephaly is uncertain; with prevalence rates ranging from 1% to 17%. Most studies are retrospective and contain more adult than pediatric patients, there is a need for more prospective pediatric studies.Methods: We recruited 131 patients (108 males, 23 females) with ASD and macrocephaly between the ages of 3 and 18 from five child and adolescent psychiatry clinics in Turkey from July 2018 to December 2019. We defined macrocephaly as occipito‐frontal HC size at or greater than 2 standard deviations (SD) above the mean for age and sex on standard growth charts. PTEN gene sequence analysis was performed using a MiSeq next generation sequencing (NGS) platform, (Illumina).Conclusion: PTEN gene sequence analyses identified three pathogenic/likely pathogenic mutations [NM_000314.6; p.(Pro204Leu), (p.Arg233*) and novel (p.Tyr176Cys*8)] and two variants of uncertain significance (VUS) [NM_000314.6; p.(Ala79Thr) and c.*10del]. We also report that patient with (p.Tyr176Cys*8) mutation has Grade 1 hepatosteatosis, a phenotype not previously described. This is the first PTEN prevalence study of patients with ASD and macrocephaly in Turkey and South Eastern Europe region with a largest homogenous cohort. The prevalence of PTEN mutations was found 3.8% (VUS included) or 2.29% (VUS omitted). We recommend testing for PTEN mutations in all patients with ASD and macrocephaly.