Peiqing He, Sini Zou, Jianxiong Chen, Meiyi Wang, Peng Lin, Jiwu Lou, Zhanying Ma, Zhen Li, Tizhen Yan
Dongguan Maternal and Child Health Care Hospital.
China
European Journal of Medical Genetics
Eur J Med Genet 2025;
DOI: 10.1016/j.ejmg.2025.105060
Abstract
Pathogenic variants in the NONO gene (MIM #300084) are responsible for X-linked syndromic intellectual developmental disorder-34 (MRXS34, MIM #300967) characterized by macrocephaly, dysmorphic facial features, global developmental delay, hypotonia, heart anomalies, and mild structural brain abnormalities. This report describes a 3-month-old male and a 7-month-old female presenting with microcephaly, dysmorphic facial features, developmental delay, hypotonia, congenital heart defects, abnormal kidney ultrasound, and abnormal cranial MRI findings. The male exhibited left ventricular noncompaction (LVNC), while the female also had abdominal distension and chronic constipation. Whole-exome sequencing (WES) was employed to identify the causative variants. A systematic review of MRXS34 clinical phenotypes was also conducted. WES revealed a novel maternally inherited Xq13.1 hemizygous deletion, encompassing exons 6-13 of the NONO gene in the male, and a recurrent de novo heterozygous c.344G>A (p.Arg115His) variant in NONO in the female. The latter demonstrated extreme X-chromosome inactivation (XCI) skewing. To date, 33 unrelated male cases of MRXS34 have been documented, and 27 NONO variants, have been identified worldwide. The phenotypes in our patients overlap with those previously reported or closely resemble those of MRXS34. Macrocephaly, corpus callosum anomalies, and LVNC exhibit relatively high penetrance but tend to worsen with age. Additionally, dysplastic pulmonary valve/pulmonary hypertension and recurrent chronic constipation episodes may be integral to an alternative NONO-related disorder. This study expands the phenotypic and allelic diversity of NONO-related disorder by providing further genotype-phenotype correlations from two additional cases. The co-occurrence of a NONO variant with extreme XCI skewing likely underpins the pathogenicity of this rare female case, which presents with severe phenotypes akin to those seen in male patients with MRXS34.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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