Abstract
Purpose
Spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising 8 with SINO and 4 with an autosomal recessive condition attributed to biallelic KIDINS220 variants.
Methods
In our international cohort, we have included 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form. We assessed the clinical and molecular data of our cohort and previously reported individuals and, based on functional experiments, reached a better understanding of the pathogenesis behind the KIDINS220-related disease.
Results
Using fetal tissue and in vitro assays, we demonstrate that the variants generate KIDINS220 truncated forms that mislocalize in punctate intracellular structures, with decreased levels of the full-length protein, suggesting a trans-dominant negative effect. A total of 92% had their diagnosis within 3 years, with symptoms of developmental delay, spasticity, hypotonia, lack of eye contact, and nystagmus. We identified a KIDINS220 variant associated with fetal hydrocephalus and show that 58% of examined individuals present brain ventricular dilatation. We extend the phenotypic spectrum of SINO syndrome to behavioral manifestations not previously highlighted.
Conclusion
Our study provides further insights into the clinical spectrum, etiology, and predicted functional impact of KIDINS220 variants.
Spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising 8 with SINO and 4 with an autosomal recessive condition attributed to biallelic KIDINS220 variants.
Methods
In our international cohort, we have included 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form. We assessed the clinical and molecular data of our cohort and previously reported individuals and, based on functional experiments, reached a better understanding of the pathogenesis behind the KIDINS220-related disease.
Results
Using fetal tissue and in vitro assays, we demonstrate that the variants generate KIDINS220 truncated forms that mislocalize in punctate intracellular structures, with decreased levels of the full-length protein, suggesting a trans-dominant negative effect. A total of 92% had their diagnosis within 3 years, with symptoms of developmental delay, spasticity, hypotonia, lack of eye contact, and nystagmus. We identified a KIDINS220 variant associated with fetal hydrocephalus and show that 58% of examined individuals present brain ventricular dilatation. We extend the phenotypic spectrum of SINO syndrome to behavioral manifestations not previously highlighted.
Conclusion
Our study provides further insights into the clinical spectrum, etiology, and predicted functional impact of KIDINS220 variants.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 101219 |
| Tidsskrift | Genetics in Medicine |
| Vol/bind | 26 |
| Udgave nummer | 11 |
| Antal sider | 14 |
| ISSN | 1098-3600 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:The authors extend their heartfelt gratitude to all the patients and family members who generously participated in the study. Their willingness, cooperation and trust have been an invaluable contribution to the advancing clinical and medical knowledge of this rare disease. The authors thank Dr Giampietro Schiavo (UCL Queen Square Institute of Neurology, London, UK) for providing the KNA antibody. F.C. was partially supported by the Italian Ministry of University and Research (MUR), Call PRIN 2022 - Prot. 20224YX5ZX - Investigating common pathogenic mechanisms of rare genetic hereditary spastic paraplegia - CUP J53D23010800006\u2014Funded by the European Union\u2014Next-Generation EU (M4.C2.1.1). T.I. was supported by grant PID2020-115218RB-I00, funded by MCIN/AEI/ 10.13039/501100011033 and by CB06/05/1122 grant funded by Centro de Investigaci\u00F3n Biom\u00E9dica en Red de Enfermedades Neurodegenerativas (CIBERNED, Instituto de Salud Carlos III, Spain) funded by Ministry of Science, Innovation and Universities (Ministerio de Ciencia, Innovaci\u00F3n y Universidades) and supported in part by \u201CERDF A way of making Europe\u201D funds (European Union). Conceptualization: M.A. F.C. T.I. P.S.-V. E.\u00D8.; Investigation: A.K.-R. C.L.-M. J.P.-U.; Formal Analysis and Resources: M.A. F.C. A.K.-R. C.L.-M. J.P.-U. F.C.C. M.O.B. C.F. M.K. S.B. S.P.-L. L.M. B.K. A.A. D.G. R.S. F.M.S. A.S. M.V. M.G. J.M. C.S. V.K.G. V.M.S. I.T. T.P. K.B. A.L. J.G. C.E.K. N.M. P.S.-V. T.I. E.\u00D8.; Visualization: M.A. F.C. T.I. A.K.-R. C.L.-M.; Supervision: M.A. F.C. T.I. P.S.-V. E.\u00D8.; Project Administration: M.A.; Writing-original draft: M.A. F.C. T.I. P.S.-V. E.\u00D8. A.K.-R. C.L.-M.; Writing-review and editing: all co-authors. Morten Alstrup: http://orcid.org/0000-0002-7338-088X, Fabrizia Cesca: http://orcid.org/0000-0003-2190-6314, Teresa Iglesias: http://orcid.org/0000-0002-4326-9005, All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from the probands or their legal representatives for this study. All individuals included provided informed consent for their participation in the study and use of photographs and/or images.
Funding Information:
F.C. was partially supported by the Italian Ministry of University and Research (MUR), Call PRIN 2022-Investigating common pathogenic mechanisms of rare genetic hereditary spastic paraplegia-CUP J53D23010800006\u2014Funded by the European Union\u2014Next-Generation EU (M4.C2.1.1). T.I. was supported by grant PID2020-115218RB-I00, funded by MCIN /AEI/ 10.13039/501100011033 and by CB06/05/1122 Centro de Investigaci\u00F3n Biom\u00E9dica en Red de Enfermedades Neurodegenerativas (CIBERNED, Instituto de Salud Carlos III , Spain) funded by MCIU and supported in part by \u201C ERDF A way of making Europe\u201D funds.
Publisher Copyright:
© 2024 American College of Medical Genetics and Genomics