Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies

Article metrics

Abstract

Purpose

To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes.

Methods

Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes.

Results

We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant.

Conclusion

Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Magnetic resonance image (MRI) features of the patients with identified causal or strongly candidate pathogenic variants.
Fig. 2: Identification of likely pathogenic variants in PIGS.
Fig. 3: SKOR2 pathogenic variant in patient 15.

References

  1. 1.

    Batten FE. Congenital cerebellar ataxia. Clin J. 1903;22:81.

  2. 2.

    Batten FE. Ataxia in childhood. Brain. 1905;28:484.

  3. 3.

    Ingram TTS. Congenital ataxic syndromes in cerebral palsy. Acta Paediatr. 1962;51:209–21.

  4. 4.

    Harding AE. Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia. J Neurol Neurosurg Psychiatry. 1981;44:503–8.

  5. 5.

    Steinlin M. Non-progressive congenital ataxia. Brain Dev. 1998;20:199–208.

  6. 6.

    Al-Maawali A, Blaser S, Yoon G. Diagnostic approach to childhood-onset cerebellar atrophy: a 10-year retrospective study of 300 patients. J Child Neurol. 2012;27:1121–32.

  7. 7.

    Poretti A, Wolf NI, Boltshauser E. Differential diagnosis of cerebellar atrophy in childhood: an update. Neuropediatrics. 2015;46:359–70.

  8. 8.

    Ohba C, Osaka H, Iai M, et al. Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood. Neurogenetics. 2013;14:225–32.

  9. 9.

    Fogel BL, Lee H, Deignan JL, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014;71:1237–46.

  10. 10.

    Pyle A, Smertenko T, Bargiela D, et al. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain J Neurol. 2015;138:276–83.

  11. 11.

    Landrum MJ, Lee JM, Benson M, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44:862–8.

  12. 12.

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

  13. 13.

    Gulsuner S, Tekinay AB, Doerschner K, et al. Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred. Genome Res. 2011;21:1995–2003.

  14. 14.

    Akizu N, Cantagrel V, Zaki MS, et al. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction. Nat Genet. 2015;47:528–34.

  15. 15.

    Pilliod J, Moutton S, Lavie J, et al. New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. Ann Neurol. 2015;78:871–86.

  16. 16.

    Huang L, Chardon JW, Carter MT, et al. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet J Rare Dis. 2012;7:67.

  17. 17.

    Travaglini L, Nardella M, Bellacchio E, et al. Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia. Eur J Paediatr Neurol. 2017;21:450–6.

  18. 18.

    Gburek-Augustat J, Beck-Woedl S, Tzschach A, et al. Epilepsy is not a mandatory feature of STXBP1-associated ataxia-tremor-retardation syndrome. Eur J Paediatr Neurol. 2016;20:661–5.

  19. 19.

    Di Meglio C, Lesca G, Villeneuve N, et al. Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases. Epilepsia. 2015;56:1931–40.

  20. 20.

    Saunders CJ, Miller NA, Soden SE, et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012;4:154ra135.

  21. 21.

    Srivastava S, Olson HE, Cohen JS, et al. BRAT1 mutations present with a spectrum of clinical severity. Am J Med Genet A. 2016;170:2265–73.

  22. 22.

    Verkerk AJMH, Schot R, Dumee B, et al. Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet. 2009;85:40–52.

  23. 23.

    Edvardson S, Oz S, Abulhijaa FA, et al. Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy. J Med Genet. 2013;50:118–23.

  24. 24.

    Pippucci T, Parmeggiani A, Palombo F, et al. A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. PLoS ONE. 2013;8:e82154.

  25. 25.

    Enns GM, Shashi V, Bainbridge M, et al. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med. 2014;16:751–8.

  26. 26.

    Lam C, Ferreira C, Krasnewich D, et al. Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet Med. 2017;19:160–8.

  27. 27.

    Kinoshita T. Biosynthesis and deficiencies of glycosylphosphatidylinositol. Proc Jpn Acad Ser B Phys Biol Sci. 2014;90:130–43.

  28. 28.

    Um JW, Ko J. Neural Glycosylphosphatidylinositol-Anchored Proteins in Synaptic Specification. Trends Cell Biol. 2017;27:931–45.

  29. 29.

    Krawitz PM, Schweiger MR, Rödelsperger C, et al. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat Genet. 2010;42:827–9.

  30. 30.

    Fauth C, Steindl K, Toutain A, et al. A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2. Am J Med Genet A. 2016;170A:392–402.

  31. 31.

    Kvarnung M, Steindl K, Toutain A, et al. A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. J Med Genet. 2013;50:521–8.

  32. 32.

    Nguyen TTM, Murakami Y, Sheridan E, et al. Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia. Am J Hum Genet. 2017;101:856–65.

  33. 33.

    Wang B, Harrison W, Overbeek PA, et al. Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development. Development. 2011;138:4487–97.

  34. 34.

    Nakatani T, Minaki Y, Kumai M, et al. The c-Ski family member and transcriptional regulator Corl2/Skor2 promotes early differentiation of cerebellar Purkinje cells. Dev Biol. 2014;388:68–80.

  35. 35.

    Sawyer SL, Schwartzentruber J, Beaulieu CL, et al. Exome sequencing as a diagnostic tool for pediatric-onset ataxia. Hum Mutat. 2014;35:45–49.

  36. 36.

    Masnada S, Hedrich UBS, Gardella E, et al. Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. Brain. 2017;140:2337–54.

  37. 37.

    Bushart DD, Shakkottai VG. Ion channel dysfunction in cerebellar ataxia. Neurosci Lett 2018. https://doi.org/10.1016/j.neulet.2018.02.005.

  38. 38.

    Davies A, Kadurin I, Alvarez-Laviada A, et al. The alpha2delta subunits of voltage-gated calcium channels form GPI-anchored proteins, a posttranslational modification essential for function. Proc Natl Acad Sci USA. 2010;107:1654–9.

  39. 39.

    Minaki Y, Nakatani T, Mizuhara E, et al. Identification of a novel transcriptional corepressor, Corl2, as a cerebellar Purkinje cell-selective marker. Gene Expr Patterns. 2008;8:418–23.

Download references

Author information

Correspondence to Lydie Burglen MD, PhD.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • Congenital ataxia
  • exome sequencing,
  • Cerebellar atrophy
  • Early infantile epileptic encephalopathies
  • Pathophysiology

Further reading