Case Study Shows ITPR1 Variant Associated With Spinocerebellar Ataxia Type 29


In a recent case study, clinical exome sequencing exposed a heterozygous missense mutation in the ITPR1 gene where patients showed craniofacial abnormalities as well as spinocerebellar ataxia-like syndrome.

Gholson Lyon, MD, PhD, human geneticist and a child, adolescent and adult psychiatrist at the Institute for Basic Research in Developmental Disabilities

Gholson Lyon, MD, PhD

A case study published in Molecular Case Studies identified an ITPR1 variant associated with spinocerebellar ataxia (SCA29) that was presumed to be inherited via parental mosaicism. According to the investigators, these findings provide additional evidence for germline mosaic inheritance of SCA29 and expand the clinical phenotype of the syndrome.1

The case report focused on a family with 3 individuals that had heterozygous missense c.800C > T (predicted p.Thr267Met) on exome sequencing. The patients also presented clinically with a SCA29-like syndrome including having different degrees of ataxia, developmental delay, apparent intellectual disability, and craniofacial involvement, which authors noted is an uncommon finding in individuals with SCA29.

Top Clinical Takeaways

  • The study highlights the atypical inclusion of craniofacial features in patients with SCA29, broadening the understanding of the syndrome's clinical phenotype.
  • The potential germline mosaicism in the ITPR1 gene underscored the importance of genetic counseling, even when a variant is initially labeled as 'de novo,' emphasizing potential risks for future pregnancies.
  • Despite limitations, the findings contribute to the growing genetic evidence linking ITPR1 mutations to ataxia, advocating for its consideration in gene panels for ataxia-related diagnostic testing.

“We reported 1 family with 3 children with mutation in the gene ITPR1, but where the parents did not have the mutation in DNA isolated from their blood. We write in the paper that this likely resulted from germline mosaicism in 1 of the parents, i.e. in the sperm or ovaries, but not present in some other tissues, including blood, from that parent” senior author Gholson Lyon, MD, PhD, human geneticist and a child, adolescent and adult psychiatrist at the Institute for Basic Research in Developmental Disabilities, told NeurologyLive®. “Although such a thing has been known for years, it is always worth reminding clinicians about this, particularly so that parents can be warned of possible recurrence in future pregnancies, even if the variant is labeled as ‘de novo’ in the first affected child. This is why it is essential for genetic counseling to always occur when genetic results are being given back to families.”

READ MORE: Case Study Reveals Paroxysmal Ataxia Potentially Associated With Late-Onset Spinocerebellar Ataxia-27B

Investigators performed chromosomal microarrays and collected whole blood samples from the mother, father, proband, 2 affected siblings, and the unaffected sibling. The researchers performed direct sequencing on the ABI3130 automatic sequencer and then analyzed the sequence data from the patients. Authors noted that the ITPR1 variant was identified using clinical exome sequencing and validated with Sanger sequencing.

The initial patient, the proband, presented between 12 and 14 months of age with developmental and neurological concerns. Original examination showed mild craniofacial dysmorphism and neurological signs such as upward gaze preference and hypotonia. Over the years, the patient showed developmental delays, speech difficulties, and physical features. Examinations at different ages revealed a progression of symptoms, including cerebellar dysfunction, wide-based gait, hyperreflexia, and positive Gower sign. A follow-up neurological examination between the ages of 22 and 24 indicated persistent cerebellar dysfunction, dysmetria, and leukocoria.

The affected sister sibling had developmental delays and neurological symptoms, sharing similarities with a proband but of milder intensity. The patient showed motor and speech delays, achievement of developmental milestones later than average, and presented craniofacial features. Physical examinations showed both hypertonic and hypotonic characteristics in different body regions. Follow-up visits showed improvements in some developmental progress, but neurological symptoms persisted, including esotropia, jerky movements, and a wide-based ataxic gait. At re-evaluation between 22 and 24 years, the patient displayed signs of cerebellar dysfunction, peroneal muscular atrophy, dysarthria, and a positive Babinski response.

The other affected sister sibling, presented with developmental abnormalities between 4 and 6 months of age. Initially, the patient showed delayed developmental milestones, craniofacial abnormalities, poor eye contact, and neurological signs. As the patient aged, partial improvement showed in some motor skills, and the patient sat unassisted and crawled between 13 and 14 months of age. Additional later evaluations between 14 and 16 months and between 16 and 18 showed fluctuating tones, gait ataxia, right-hand dystonia, dysmetria, nystagmus, and dysarthria. Despite an improvement in some symptoms, the patient exhibited mild neurological issues.

“This provides further evidence for the role of mutations in this gene in people presenting with ataxia,” Lyon, also a professor at Roseman University School of Medicine, and City University of New York, told NeurologyLive.

All told, limitations of this study included sporadic clinic and follow-up visits with frequent loss of follow-up as well, which is known as a frequent challenge at medical genetics clinics.2 Despite the authors attempts to reach out to the family prior to the submission of the manuscript, they received no response. Additionally, authors noted that there was varying detail and description of craniofacial abnormalities in siblings, clinicians, and subsequent visits. The investigators also were not able to confirm the presence of the pathogenic variant in parental gametes given the limitations of detecting germline mosaicism. Furthermore, authors noted that the contribution of the variant to the proband's phenotype is uncertain despite no clinical syndromes associated with genes in the 5q33.1 → q33.1 duplication.

“We reported the finding to the community, but unfortunately are not able to pursue this further because of lack of funding. We hope that other investigators will develop animal models or patient-derived stem cell lines, which can be helpful for understanding more about the biology of the gene,” Lyon added. “In addition, the accumulating genetic evidence might help to get this gene added to any gene panels being performed for anyone presenting with ataxia, given that sometimes gene panels are more readily approved by insurance, instead of exome sequencing, which is still not routinely approved by many insurance companies.”

1. Kleyner R, Ung N, Arif M, et al. ITPR1-associated spinocerebellar ataxia with craniofacial features-additional evidence for germline mosaicism. Cold Spring Harb Mol Case Stud. 2024;9(4):a006303. Published 2024 Jan 10. doi:10.1101/mcs.a006303
2. Esmer C, Urraca N, Carnevale A, Del Castillo V. Patient follow-up is a major problem at genetics clinics. Am J Med Genet A. 2004;125A(2):162-166. doi:10.1002/ajmg.a.20303
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