Jul 2026· Brain & development (Tokyo. 1979)· Vol 48 4, pp.
104570
· 0 citations· 16 references
Medicine
TL;DR
The findings underscore RNU4-2 as a major cause of NDDs in ES-negative cases and further delineate the phenotypic spectrum of ReNU syndrome.
Abstract
INTRODUCTION
ReNU syndrome is a neurodevelopmental disorder (NDD) caused by pathogenic variants in RNU4-2, a non-coding gene encoding the U4 small nuclear RNA (snRNA). As a critical component of the major spliceosome, U4 snRNA is essential for pre-mRNA splicing; however, RNU4-2 is not captured by conventional exome sequencing (ES), often leaving affected individuals undiagnosed.
Methods
To evaluate the prevalence and clinical impact of RNU4-2 variants, we performed genome sequencing in 95 patients with NDDs in whom prior ES had failed to identify a causative variant.
Results
We identified a recurrent RNU4-2 variant (NR_003137.3:n.64_65insT) in five patients (5.3%), four of whom are described here. All variants occurred de novo. Affected individuals exhibited severe intellectual disability, developmental delay, microcephaly, short stature, and consistent brain MRI findings, including ventricular enlargement and corpus callosum thinning. Distinctive facial features involving the lips and philtrum were consistently observed, including a characteristic combination of a tented upper lip with an exaggerated Cupid's bow, an everted lower lip, and a horizontally oriented philtrum. In addition, transient limb edema and rib dysplasia may expand the phenotypic spectrum. The n.64_65insT variant, located within the functional T-loop of the U4 snRNA, appears to be associated with more severe cognitive impairment than other RNU4-2 variants.
Conclusions
Our findings underscore RNU4-2 as a major cause of NDDs in ES-negative cases and further delineate the phenotypic spectrum of ReNU syndrome. Recognition of the characteristic "lip and philtrum gestalt" serves as a vital clinical clue, prompting targeted genetic evaluation for this frequently overlooked disorder.
More than 70% of non-obstructive azoospermia (NOA) cases remain idiopathic, and the underlying genetic causes need to be investigated. In this study, we aimed to identify genes and variants associated with the etiology of NOA. Two NOA patients from consanguineous families, with normal karyotypes and no Y-chromosome microdeletions, were selected for whole-genome sequencing (WGS). Candidate variants were validated by Sanger sequencing. Structural protein modeling and assessment of mutation-induced changes in molecular interactions were performed using SWISS-MODEL and AlphaFold. We identified a candidate homozygous missense variant (c.899C>T, p.(Ser300Phe); rs375931805) in SOX30 in one patient; this transcription factor is highly expressed in the testis. In the second patient, a homozygous missense variant (c.1472C>T, p.(Thr491Met); rs746902232) in RNF220 and a hemizygous missense variant (c.2354A>G, p.(Gln785Arg) in the X-linked AKAP4 gene were simultaneously detected. Previous studies have shown that SOX30 knockout in mice leads to meiosis I arrest and impaired spermiogenesis. AKAP4 is exclusively expressed in the testis, and missense variants have been reported in different forms of male infertility. The co-occurrence of variants in AKAP4 and RNF220 may suggest an oligogenic etiology of NOA and contribute to the phenotypic variability associated with AKAP4 variants.
Razieh Ebrahimi Askari, A. Malcher, Fateme Sefid et al.· International Journal of Mol...· 0 citations
The genotypic and phenotypic spectrum of NMOAS is expanded, the pathogenic role of this variant in splicing dysregulation is confirmed, and the need for long-term monitoring of emerging comorbidities in affected patients is emphasized.
Yue Shen, Yunyu Zhou, Chao Lu et al.· Clinical Genetics· 0 citations
Patients with suspected monogenic disorders often remain undiagnosed after exome sequencing. We report a family with two sisters affected by a complex spastic paraplegia. Initial exome sequencing had identified monoallelic pathogenic nonsense variants in AP4S1 and AP4B1, subunits of the adaptor protein complex 4 (AP‐4), suggesting digenic inheritance. As digenic inheritance has not been established for AP‐4–associated disorders, we applied a multiomics approach including genome sequencing, RNA sequencing and proteomics to clarify the genetic cause. By RNA sequencing a predicted synonymous variant (NM_006594.5:c.969G > A), compound heterozygous to the nonsense variant in AP4B1 and previously considered as benign, was re‐prioritized as aberrant splicing was demonstrated. Proteomics showed reduced abundance of AP‐4 components AP4B1 and AP4M1 and an upregulation of the cargo protein ATG9A, confirming AP‐4 deficiency. Although the AP4S1 variant resulted in nonsense‐mediated decay, the identification of biallelic causative variants in AP4B1 established the diagnosis of monogenic “Spastic paraplegia 47, autosomal recessive” while the initial hypothesis of digenic inheritance was refuted. This study illustrates the value of multiomics approaches in the diagnostic workflow of rare diseases and the potential for pathogenicity of synonymous variants.
Susann Badmann, A. Saparov, P. Harrer et al.· Human Mutation· 0 citations
This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder and indicates growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies.
Yaping Shen, Rongrong Pan, Chen Liu et al.· Genes· 0 citations
The novel NR2F1 variant was classified as likely pathogenic according to ACMG guidelines, confirming the diagnosis of BBSOAS and the ARF3 variant, identified as a secondary finding of uncertain clinical significance, is unlikely to account for the patient's phenotype.
Sina Babaei, Haneieh Honarmand, Mortaza Bonyadi et al.· Molecular Biology Reports· 0 citations