“Severe intellectual disability with cardiac and dermatologic involvement due to homozygous METTL23 frameshift mutation: a case report of two Turkish sisters”
This is the first report of the c.470_471del (p.Leu157ArgfsTer4) variant in a homozygous state, providing novel insights into genotype–phenotype correlations and significantly broaden the known clinical spectrum of METTL23-associated disorders.
The EEFSEC gene encodes eukaryotic elongation factor selenocysteine-tRNA-specific, an essential component of the selenoprotein biosynthesis machinery required for normal neurodevelopment. Biallelic EEFSEC variants have recently been associated with a rare autosomal recessive neurodevelopmental disorder with variable neurological severity. Here, we describe a Turkish proband carrying the recurrent homozygous EEFSEC (NM_021937.5) variant c.1169A>C; p.Asp390Ala, together with his younger brother, who was identified with the same homozygous variant through familial testing. The proband presented with intellectual disability, delayed motor and expressive language development, mild hypotonia, subtle dysmorphic features, and self-limited early childhood febrile seizures. Compared with previously reported Turkish patients carrying the same variant, his absence of ocular motor involvement, normal neuroimaging, lack of persistent epileptiform abnormalities, and partial developmental gains suggest a relatively milder neurological presentation. The younger brother was initially identified before overt neurological manifestations and subsequently showed delayed expressive language development during early follow-up. This report provides comparative data on the recurrent EEFSEC p.Asp390Ala variant and highlights the value of familial testing, early molecular diagnosis, and longitudinal developmental monitoring in families with confirmed biallelic EEFSEC variants.
Kubra Ates, Bülent Kara· American Journal of Medical...· 0 citations
A novel homozygous missense variant in RNF216 gene c.1055T>G (p.(Phe352Cys)) in three siblings with Gordon Holmes syndrome is reported, contributing to the limited knowledge of GHS and highlighting the importance of hypogonadotropic hypogonadism treatment and close observation of neurological symptoms that may develop over time.
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
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
A retrospective multicenter case series of seven previously unreported individuals with heterozygous FBXW7 variants identified through clinical genetic testing expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance.
Salvatore Savasta, F. Comisi, G. Dell’Isola et al.· Journal of Neurodevelopmenta...· 0 citations
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