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Broadening the Phenotype and Genotype Spectrum of Novel Mutations in Pontocerebellar Hypoplasia With a Comprehensive Molecular Literature Review Publisher Pubmed



Ghasemi MR1, 2 ; Tehrani Fateh S3 ; Moeinafshar A3 ; Sadeghi H1 ; Karimzadeh P4 ; Mirfakhraie R1 ; Rezaei M5 ; Hashemigorji F5 ; Rezvani Kashani M4 ; Fazeli Bavandpour F2 ; Bagheri S2, 6 ; Moghimi P2, 6 ; Rostami M2 ; Madannejad R2 Show All Authors
Authors
  1. Ghasemi MR1, 2
  2. Tehrani Fateh S3
  3. Moeinafshar A3
  4. Sadeghi H1
  5. Karimzadeh P4
  6. Mirfakhraie R1
  7. Rezaei M5
  8. Hashemigorji F5
  9. Rezvani Kashani M4
  10. Fazeli Bavandpour F2
  11. Bagheri S2, 6
  12. Moghimi P2, 6
  13. Rostami M2
  14. Madannejad R2
  15. Roudgari H2, 5
  16. Miryounesi M1, 2, 5
Show Affiliations
Authors Affiliations
  1. 1. Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  2. 2. Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  3. 3. School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  4. 4. Pediatric Neurology Department, Mofid Children’s Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  5. 5. Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  6. 6. School of Medicine, Islamic Azad University Tehran Medical Sciences, Tehran, Iran

Source: BMC Medical Genomics Published:2024


Abstract

Background: Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH. Methods: Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature review to outline the genetic features of the various subtypes of PCH. Results: This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9. Conclusions: This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH. © The Author(s) 2024.
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