A De Novo Missense NPTX1 Variant in an Individual with Infantile‐Onset Cerebellar Ataxia

Most recently, three different missense variants in the NPTX1 gene were described to cause late‐onset cerebellar ataxia with an autosomal dominant inheritance pattern.^{1, 2} Here, we report on a child affected by early‐onset ataxia and cerebellar atrophy since infancy, who carries a novel heterozygous de novo missense variant in NPTX1, affecting a highly conserved residue of pentraxin (Gln370Arg).

The patient, a currently 6‐year‐old girl, is the second child of nonconsanguineous parents with an unremarkable family history. After an uneventful pregnancy and uncomplicated delivery, developmental progress (walking, speech, and social skills) was reported normal until the age of 21 months. At this time, unsteadiness, irritability, and sleeping problems were noted, and a neurological assessment was initiated. By the age of 2 years, she developed truncal and limb ataxia with an inability to walk and loss of acquired speech skills. The first magnetic resonance imaging (MRI) was performed at the age of 25 months, demonstrating enlarged fissures of cerebellar vermis and hemispheres, suggestive of cerebellar atrophy. The cerebellar cortex had increased fluid‐attenuated inversion recovery hyperintensity, compared with the cerebral cortex. A second MRI, performed at 40 months, showed the cerebellar vermis atrophy mildly more accentuated (Fig. 1); however, this is a common nonspecific finding in many pediatric‐onset ataxias. ³ At the age of 6 years generalized epileptic seizures with electroencephalographic correlate were diagnosed and treated with lacosamide.

FIG 1.

Neuroimaging at the age of 40 months. (A) Sagittal T1‐weighted image demonstrating markedly enlarged fissures of the cerebellar vermis and preserved pontine protuberance. (B) Axial T1‐weighted image showing enlarged fissures in vermis and cerebellar hemispheres. (C) Axial FLAIR sequence with evidence of mild hyperintensity of the cerebellar cortex (compared with cerebral cortex). FLAIR, fluid‐attenuated inversion recovery.

Based on the clinical diagnosis of suspected genetic ataxia and vermis atrophy on MRI, exome sequencing (using Agilent SureSelect Human All Exon V6 and Illumina HiSeq 150 bp paired‐end sequencing technology) was performed at the age of 30 months in 2017 but failed to identify (likely) pathogenic variants in any gene known to be associated with ataxia or childhood‐onset neurological disorders at that time. Following the publication of variants in a novel gene (NPTX1) to be associated with ataxia, ¹ the archived exome data were reevaluated by querying for variant calls in this gene. We indeed identified a hitherto‐unreported missense variant within exon 5 of the NPTX1 gene, NM_002522.4:c.1109A>G(hg19_chr17:g.78444803T>C), predictably leading to the substitution of a highly conserved amino acid residue within the pentraxin domain: p.(Gln370Arg). Subsequent confirmation by conventional DNA sequencing and targeted segregation analysis in parental DNA revealed that the variant occurred de novo (see Appendix S1), suggestive of parental germline mosaicism. This missense variant was absent from more than 250,000 control alleles in gnomAD and more than 3400 alleles from in‐house‐sequenced individuals affected with various clinical conditions. In silico evaluation predicted a likely pathogenic effect of the variant (CADD phred score of 27.1, DANN score of 0.999, and ClinPred score of 0.994), with consistent results across different algorithms.^{4, 5, 6}

Overall, our results support the notion that de novo variants in NPTX1 might also be implicated in pediatric‐onset ataxia. This case underlines the importance of holistic diagnostic approaches in neurologic conditions with suspected hereditary disease. Finally, this case also demonstrates how continuous reevaluation of next‐generation sequencing data after publication of novel relevant disease‐causing genes can shorten the path to a genetic diagnosis for individuals affected by rare diseases and their families.

Author Roles

1. Research project: A. Conception, B. Organization, C. Execution;

2. Manuscript: A. Writing of the first draft, B. Review and critique.

J.S.: 1A, 1C, 2A, 2B

S.S.: 1A, 1C, 2B

E.B.: 1A, 1C, 2B

M.F.: 1A, 1B, 1C, 2B

W.M.S.: 1A, 1B, 1C, 2A, 2B

Full financial disclosures for the previous 12 months

The authors state no financial disclosures.

Supporting information

APPENDIX S1. Supporting Information

Data Availability Statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.