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Fulltext RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort

Matalon DR, Duker AL, Arriaga TM, Russell K, Mendez HR, Bonner DE, et al.

Genet Med, 2026 Oct;28(10):102633.
PMID: 42322193 DOI: 10.1016/j.gim.2026.102633

PURPOSE: We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene.
METHODS: Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals.
RESULTS: We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature.
CONCLUSION: This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.

Matched MeSH terms: Microcephaly/genetics
Zika virus in Vietnam, Laos, and Cambodia: are there health risks for travelers?

Dinh TC, Bac ND, Minh LB, Ngoc VTN, Pham VH, Vo HL, et al.

Eur J Clin Microbiol Infect Dis, 2019 Sep;38(9):1585-1590.
PMID: 31044332 DOI: 10.1007/s10096-019-03563-6

Vietnam, Laos, and Cambodia have reported first cases of Zika virus (ZIKV) infection since 2010 (Cambodia) and 2016 (Vietnam and Laos). One case of ZIKV-related microcephaly was recognized among a hundred infected cases in these areas, raising a great concern about the health risk related to this virus infection. At least 5 cases of ZIKV infection among travelers to Vietnam, Laos, and Cambodia were recorded. It is noticeable that ZIKV in these areas can cause birth defects. This work aims to discuss the current epidemics of ZIKV in Vietnam, Laos, and Cambodia and update the infection risk of ZIKV for travelers to these areas.

Matched MeSH terms: Microcephaly/virology
Fulltext RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Reijnders MRF, Ansor NM, Kousi M, Yue WW, Tan PL, Clarkson K, et al.

Am J Hum Genet, 2017 Sep 07;101(3):466-477.
PMID: 28886345 DOI: 10.1016/j.ajhg.2017.08.007

RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.

Matched MeSH terms: Microcephaly/genetics*; Microcephaly/pathology
Fulltext Cri-du-chat syndrome: application of array cgh in diagnostic evaluation

Juriza, I., Sharifah Azween, S.O., Azli, I., Zarina, A.L., Mohd Fadly, M.A., Zubaidah, Z., et al.

Medicine & Health, 2010;5(2):108-113.
MyJurnal

The human genome contains many submicroscopic copy number variations which includes deletions, duplications and insertions. Although conventional karyotyping remains an important diagnostic tool in evaluating a dysmorphic patient with mental retardation, molecular diagnostic technology such as array comparative genomic hybridization (aCGH) has proven to be sensitive and reliable in detecting these submicroscopic anomalies. A 3 month-old infant with dysmorphic facies, microcephaly and global developmental delay was referred for genetic evaluation. Preliminary karyotyping which was confounded by the quality of metaphase spread was normal; however, aCGH detected a 30.6Mb deletion from 5p15.33-p13.3. This case illustrates the usefulness of aCGH as an adjunctive investigative tool for detecting chromosomal imbalances.

Matched MeSH terms: Microcephaly
Fulltext Knowledge, Awareness, and Perception of Community Pharmacists to Zika Virus Infection in Klang Valley, Malaysia

Lim KY, Tham HW

Health Serv Insights, 2020;13:1178632920921425.
PMID: 32528223 DOI: 10.1177/1178632920921425

Background: Zika fever is a mosquito-borne disease with global health concern. It has been underreported or misdiagnosed due to its unspecific clinical manifestations, including mild-influenza like and subclinical symptoms. However, its associated serious complications which include fetal microcephaly and Guillain-Barré syndrome remained a challenge to the public health sectors. This research aimed to evaluate the knowledge, awareness, and perception toward Zika virus infection among community pharmacists in the Klang Valley of Malaysia and to determine the association between the knowledge of Zika virus infectious disease and years of community practice experience among community pharmacists in this region.
Methods: This survey research was conducted from August to December 2018 through a pre-tested, self-administration, and cross-sectional random convenient sampling at various districts in the Klang Valley. A total of 275 registered community pharmacists were involved in this study by completing a pilot-tested questionnaire. Descriptive analysis, Mann-Whitney U test, and Kruskal-Wallis H test were used to analyze the data.
Results: The knowledge toward Zika virus infection of respondents was classified into "poor" (5.1%), "basic" (70.9%), and "broad" (24.0%). Most of the participants (n = 195, 70.9%) presented with basic knowledge toward Zika virus infection. A total of 268 (97.5%) participants presented with high awareness toward Zika virus infection. The mean score of respondents' knowledge and awareness was 15.88 ± 3.61 (maximum score = 28) and 13.96 ± 1.60 (maximum score = 16), respectively. There was a statistically significant difference between the years of practice of community pharmacists and the level of knowledge toward Zika virus infection.
Conclusions: In conclusion, our respondents demonstrated a basic level of knowledge and high awareness toward Zika virus infection. Also, we highlighted some possible pitfalls in the knowledge of Zika virus infection, including the virus transmission, symptoms, diagnosis, treatment, prevention, and complications of the disease.

Matched MeSH terms: Microcephaly
Fulltext Islamic perspective on elective abortion of Zika virus infected pregnant women

Syazwani Hamdan, Mohd Rahman Omar, Mohammad Naqib Hamdan, Ummu Aiman Faisal

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):60-60.
MyJurnal

Introduction: Zika virus infection is caused by flavivirus virus and spread by Aedes mosquitoes. Since first report-ed in 1947, it spread to various countries especially in the equatorial region including Malaysia. The infection is non-fatal to an adult. However, the major risk of its infection is towards unborn baby when the mother is infected. The vertical transmission to the foetus possess various risks include the teratogenic effect that may lead to elective abortion. Thus, the objectives of this review are to discover about Zika virus and its effect on pregnant women and to evaluate Islamic perspective about elective abortion of Zika virus-infected women. Methods: This review was done through reviewing evidence from the journals, books and reports. The data were reviewed thematically according to the objectives. Results: Studies shown that Zika virus may cause miscarriage, preterm birth, microcephaly and other malformation known as Congenital Zika syndrome. This leads to a demand for elective abortion which raised Islamic ethical issue if it is permissible. In Islam, abortion is extremely prohibited once the foetus reached 120-day of con-ception unless it causes harm to the mother’s life. But, if the foetus age is less than 120-day, abortion is permissible when the pregnancy affects the mother’s health. Abortion due to foetal microcephaly and congenital malformation is prohibited. Conclusion: Effort must be taken to prevent the spread of Zika virus to reduce the need for an elective abortion through an education Muslim community regarding elective abortion.

Matched MeSH terms: Microcephaly
Severe mental retardation following asymptomatic hypoglycaemia in an infant with nesidioblastosis

Rahmah, R., Wu, L.L., Roziana, A., Swaminathan, M., Kuhnle, U.

Malaysian Journal of Child Health, 1997;9(1):93-96.
MyJurnal

Nesidioblastosis is a rare metabolic disease characterised by inappropriate insulin secretion often associated with life-threatening hypoglycaemia. While severe cases present in the newborn period, patients have been described later in infancy. Familial cases suggest an autosomal recessive trait, and recently mutations in the sulphonlurea receptor gene, possibly a regulator of insulin secretion, have been identified and associated with disease expression. We report a twin boy who developed normally until the age of six months when he was noted to regress. The boy is the older twin born to non-consanguinous parents. He presented to a hospital first at the age of 13 months with fever and generalised seizures. Low blood glucose was noted, but he recovered easily and was able to maintain euglycaemia during a 48-hour period of observation. Microcephaly and developmental delay were documented and anticonvulsant therapy was started. At 18 months, low blood glucose with high C-peptide was documented during reevaluation. Follow-ing a short trial of subcutaneous long-acting somatostatin analogue, the child was subjected to near-total pancreatectomy. The histology revealed findings consistent with nesidioblastosis. The child's condition improved but he remained significantly delayed This case emphasises the importance of recognising and treating hypoglycaemia early to avoid irreversible brain damage. It is interesting to note that the twin brother has always been well and is developmentally normal. Further studies to identify the inheritance pattern in the family would be of great interest.

Matched MeSH terms: Microcephaly
Fulltext Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, et al.

Nat Genet, 2017 Oct;49(10):1529-1538.
PMID: 28805828 DOI: 10.1038/ng.3933

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Matched MeSH terms: Microcephaly/genetics*