An identical-by-descent novel splice-donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families
Annals of Human Genetics. 2021-06-10; 85(5): 186-195
DOI: 10.1111/AHG.12437
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1. Ann Hum Genet. 2021 Sep;85(5):186-195. doi: 10.1111/ahg.12437. Epub 2021 Jun 10.
An identical-by-descent novel splice-donor variant in PRUNE1 causes a
neurodevelopmental syndrome with prominent dystonia in two consanguineous
Sudanese families.
Koko M(1), Yahia A(2)(3)(4), Elsayed LE(2)(5), Hamed AA(6), Mohammed IN(6),
Elseed MA(6), Hamad MHA(7), Babai AM(8), Siddig RA(8), Abd Allah ASI(8), Mohamed
M(9), El-Amin M(8), Esteves T(4)(10), Altmüller J(11), Toliat MR(11), Thiele
H(11), Nürnberg P(11), Salih MA(7), Ahmed AE(12), Lerche H(1), Stevanin G(4)(10).
Author information:
(1)Department of Neurology and Epileptology, Hertie Institute for Clinical Brain
Research, University of Tubingen, Tubingen, Germany.
(2)Department of Biochemistry, Faculty of Medicine, University of Khartoum,
Khartoum, Sudan.
(3)Department of Biochemistry, Faculty of Medicine, National University,
Khartoum, Sudan.
(4)Institut du Cerveau, INSERM U1127, CNRS UMR7225, Sorbonne Université, Paris,
France.
(5)College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh,
Saudi Arabia.
(6)Department of Pediatrics, Faculty of Medicine, University of Khartoum,
Khartoum, Sudan.
(7)Division of Pediatric Neurology, Department of Pediatrics, College of
Medicine, King Saud University, Riyadh, Saudi Arabia.
(8)Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
(9)Council of Diagnostic Radiology, Sudan Medical Specialization Board, Khartoum,
Sudan.
(10)Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris,
France.
(11)Cologne Center for Genomics, University of Cologne, Cologne, Germany.
(12)Department of Physiology, Faculty of Medicine, University of Khartoum,
Khartoum, Sudan.
PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative
phenotypes. Multiple pathogenic missense and stop-gain PRUNE1 variants were
identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single
splice alteration was previously reported. We investigated five patients from two
unrelated consanguineous Sudanese families with an inherited severe
neurodevelopmental disorder using whole-exome sequencing coupled with
homozygosity mapping, segregation, and haplotype analysis. We identified a
founder haplotype transmitting a homozygous canonical splice-donor variant
(NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in
all the patients. This splice variant possibly results in an in-frame deletion in
the DHH domain or premature truncation of the protein. The phenotypes of the
affected individuals showed phenotypic similarities characterized by remarkable
pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and
bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and
corroborated abnormal splicing events as a disease mechanism in PRUNE1-related
disorders. Given the phenotypes’ consistency coupled with the founder effect,
canonical and cryptic PRUNE1 splice-site variants should be carefully evaluated
in patients presenting with prominent dystonia and pyramidal dysfunction.
© 2021 John Wiley & Sons Ltd/University College London.
DOI: 10.1111/ahg.12437
PMID: 34111303 [Indexed for MEDLINE]