Abstract
Pontocerebellar hypoplasia (PCH) is currently classified into 16 subgroups. Using mostly next-generation sequencing, pathogenic variants have been identified in as many as 24 PCH-associated genes. PCH type 8 (PCH8) is a rare heterogeneous disorder. Its clinical presentation includes severe development delay, increased muscle tone, microcephaly, and magnetic resonance imaging (MRI) abnormalities such as reduced cerebral white matter, a thin corpus callosum, and brainstem and cerebellar hypoplasia. To date, only two variants in the CHMP1A gene (MIM: 164010), NM_002768.5: c.88 C > T (p.Glu30*) and c.28–13 G > A, have been identified homozygously in seven patients with PCH8 from four families (MIM: 614961). CHMP1A is a subunit of the endosomal sorting complex required for transport III (ESCRT-III), which regulates the formation and release of extracellular vesicles. Biallelic CHMP1A loss of function impairs the ESCRT-III-mediated release of extracellular vesicles, which causes impaired progenitor proliferation in the developing brain. Herein, we report a patient with PCH8 who had a homozygous CHMP1A variant, c.122delA (p.Asn41Metfs*2), which arose from segmental uniparental disomy. Although our patient had similar MRI findings to those of previously reported patients, with no progression, we report some novel neurological and developmental findings that expand our knowledge of the clinical consequences associated with CHMP1A variants.
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Change history
24 January 2023
A Correction to this paper has been published: https://doi.org/10.1038/s10038-023-01125-5
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Acknowledgements
This work was supported by AMED under grant numbers JP22ek0109486, JP22ek0109549, and JP22ek0109493 (NaM), JP20K07907 (SM), JP20K08164 (TM), JP21K07869 (EK), JP20K17936 (AF), JP20K16932 (KoH), JP21K15097 (YU), and JP20K17428 (NT); and the Takeda Science Foundation (TM and NaM). We thank Bronwen Gardner, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
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Sakamoto, M., Shiiki, T., Matsui, S. et al. A novel homozygous CHMP1A variant arising from segmental uniparental disomy causes pontocerebellar hypoplasia type 8. J Hum Genet 68, 247–253 (2023). https://doi.org/10.1038/s10038-022-01098-x
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DOI: https://doi.org/10.1038/s10038-022-01098-x
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