Abstract
DEAH-Box helicase 37 (DHX37) gene, encoding an RNA-helicase, is essential for ribosome biogenesis. Pathogenic variants in the DHX37 gene result in a spectrum of ribosomopathies ranging from neurodevelopmental disorders with possible brain, vertebral, and/or cardiac anomalies (NEDBAVC syndrome, OMIM #618731) as well as disorders of sex development. Here, we describe a young boy with DHX37-related neurodevelopmental disorder with clinical and imaging findings masquerading as cerebral palsy. A 7.5-year-old boy presented with global developmental delay and generalized chorea of 6 months duration. He was born at 37 weeks gestation after an uneventful pregnancy with a birth weight of 2668 g. He had primary microcephaly and intractable epilepsy from infancy. Examination revealed microcephaly, spastic quadriparesis, generalized choreoathetosis and dystonia. MRI of the brain revealed T2-weighted hyperintensity in bilateral corticospinal tracts, posterior limb of the internal capsule (PLIC), corona radiata, external capsule, periventricular and deep white matter, as well as subcortical cysts. Diffusion-weighted images showed high signal in bilateral corticospinal tract and PLIC. As there were red flags pointing away from cerebral palsy such as primary microcephaly, refractory seizures, late-onset movement disorder, and persistent high signal on diffusion-weighted imaging, whole genome sequencing (WGS) was sent. WGS revealed a homozygous variant c.2417G>A (p.Ser806Asn) in the DHX37 gene. He was managed with antiseizure medications and clonazepam. DHX37-related neurodevelopmental disorder should be included in the differential for cerebral palsy mimic as affected children have global developmental delay, primary microcephaly, seizures, and movement disorders and thus may masquerade as sequel of hypoxic ischemic encephalopathy.
McElreavey K, Pailhoux E, Bashamboo A. DHX37 and 46,XY DSD: A New Ribosomopathy? Sex Dev. 2022;16(2-3):194-206. doi: 10.1159/000522004. Epub 2022 Jul 14. PMID: 35835064.
Abstract
Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular regression syndrome (TRS), or anorchia. All affected children have non-syndromic forms of disorders/differences of sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains of the protein, are predicted by in silico tools to have a deleterious effect on helicase function. DHX37 is required for ribosome biogenesis in eukaryotes, and how these variants cause DSD is unclear. The relationship between DHX37 and human congenital disorders is complex as compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies. Here, we will give a brief overview of ribosome biogenesis and the role of DHX37 in this process. We will discuss variants in DHX37, their contribution to human disease in the general context of human ribosomopathies, and the possible disease mechanisms that may be involved.
Jiang W, Yu J, Mao Y, Tang Y, Cao L, Du Q, Li J, Yang J. Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development. Mol Genet Genomic Med. 2024 May;12(5):e2453. doi: 10.1002/mgg3.2453. PMID: 38769888; PMCID: PMC11106588.
Abstract
Background: 46,XY sex reversal 11 (SRXY11) [OMIM#273250] is characterized by genital ambiguity that may range from mild male genital defects to gonadal sex reversal in severe cases. DHX37 is an RNA helicase that has recently been reported as a cause of SRXY11. So far, a total of 21 variants in DHX37 have been reported in 58 cases with 46,XY disorders of sex development (DSD).
Methods: Whole exome sequencing (WES) was conducted to screen for variations in patients with 46,XY DSD. The subcellular localization of mutant DHX37 proteins was detected by immunofluorescence. And the levels of mutant DHX37 proteins were detected via Western blotting.
Results: A novel pathogenic variant of DHX37 was identified in a patient with 46,XY DSD c.2012G > C (p.Arg671Thr). Bioinformatics analysis showed that the protein function of the variant was impaired. Compared with the structure of the wild-type DHX37 protein, the number of hydrogen bonds and interacting amino acids of the variant protein were changed to varying degrees. In vitro assays revealed that the variant had no significant effect on the intracellular localization of the protein but significantly reduced the expression level of the protein.
Conclusions: Our finding further expands the spectrum of the DHX37 variant and could assist in the molecular diagnosis of 46,XY DSD patients.
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