Aug 2026· Clinical Genetics· Vol 110, pp. 502 - 507· 0 citations· 14 references
Medicine
TL;DR
Two unrelated female pediatric patients evaluated for LZTR1‐related NS following whole‐exome sequencing are reported to illustrate the marked phenotypic variability of LZTR1‐related NS and underscore that, while cardiac defects may be absent in some individuals, appropriate cardiac surveillance remains necessary.
Abstract
Noonan syndrome (NS) is a clinically heterogeneous condition caused by pathogenic variants in genes of the RAS/MAPK signaling pathway, presenting as a spectrum of phenotypic features rather than a single uniform disorder. We report two unrelated female pediatric patients evaluated for LZTR1‐related NS following whole‐exome sequencing. The first patient presented with isolated short stature, subtle dysmorphic features, and normal neurodevelopment. The second displayed multisystem involvement including developmental delay, skeletal abnormalities, and auditory processing disorder. A heterozygous pathogenic variant in LZTR1 was confirmed in the first patient, while the second carried a heterozygous LZTR1 variant of uncertain significance, rendering her diagnosis provisional. Neither patient had congenital heart defects. These cases illustrate the marked phenotypic variability of LZTR1‐related NS and underscore that, while cardiac defects may be absent in some individuals, appropriate cardiac surveillance remains necessary.
We present a family of five siblings who came to our attention with a clinical and radiological diagnosis of familial hypomyelinating leukodystrophy. Despite brain white matter abnormalities being present in all siblings, the clinical phenotype was variable: the three brothers presented with a clear-cut late-onset spastic paraplegia, whereas the two sisters displayed only mild pyramidal signs. Molecular analysis revealed a single relevant variant shared by all affected siblings, namely the likely pathogenic variant c.659C>T (p.Ser220Phe) in the GJA1 gene. Variants in this gene are generally associated with oculodentodigital dysplasia (ODDD), an autosomal dominant condition characterized by distinctive facial features and anomalies of the eyes, teeth, and digits. Neurological features are reported in about 30% of cases. In this family, ODDD manifested as a predominantly neurological phenotype. Although a clear explanation for this uncommon presentation is lacking, shared genetic modifiers, the effect of the specific variant, and a possible patient-population bias may have contributed. This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia. MRI findings may also provide a useful diagnostic clue when ODDD is suspected.
Irene Ambrosetti, Flavia Palombo, Diego D'Angeli et al.· International Journal of Mol...· 0 citations
CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.
I. Pacheva, Elena Timova, T. Todorov et al.· Frontiers in Psychiatry· 0 citations
“hemiconvulsion-hemiplegia-epilepsy syndrome” is identified as a distinct feature and potential prognostic indicator for middle domain variants in DNM1L variants, which are predominantly missense, with the middle domain as a hotspot.
Han Xu, Chao-Long Xu, Ying Zou et al.· Frontiers in Neurology· 0 citations
This case underscores that the genetic and neuropsychological identification of a neurodevelopmental disorder, together with the integration of tailored psychomotor interventions and contextual adaptations, can improve psychiatric management and daily functioning, and mitigate behavioral decline in adulthood, even following a prolonged diagnostic delay.
A. Bos-Roubos, Rosalie Te Brinke, A. Kattentidt-Mouravieva et al.· Frontiers in Psychiatry· 0 citations
This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies.
Sheyda Khalilian, Mohadeseh Fathi, Zahra Farbood et al.· Molecular Genetics and Metab...· 0 citations
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.
Ceren Yılmaz Uzman, Semra Gürsoy, F. Hazan et al.· Clinical Genetics· 0 citations
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