A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
Adolescent
Adult
Chromosome Breakpoints
Chromosomes, Human, Pair 1
/ genetics
Chromosomes, Human, Pair 17
/ genetics
Facies
Female
Fingers
/ abnormalities
Foot Deformities, Congenital
/ genetics
Gene Rearrangement
Hand Deformities, Congenital
/ genetics
Humans
In Situ Hybridization, Fluorescence
Male
Potassium Channels, Inwardly Rectifying
/ chemistry
Regulatory Sequences, Nucleic Acid
Sequence Deletion
Translocation, Genetic
Young Adult
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
received:
28
06
2021
accepted:
09
11
2021
pubmed:
26
11
2021
medline:
5
2
2022
entrez:
25
11
2021
Statut:
ppublish
Résumé
Cooks syndrome (CS) is an ultrarare limb malformation due to in tandem microduplications involving KCNJ2 and extending to the 5' regulatory element of SOX9. To date, six CS families were resolved at the molecular level. Subsequent studies explored the evolutionary and pathological complexities of the SOX9-KCNJ2/Sox9-Kcnj2 locus, and suggested a key role for the formation of novel topologically associating domain (TAD) by inter-TAD duplications in causing CS. Here, we report a unique case of CS associated with a de novo 1;17 translocation affecting the KCNJ2 locus. On chromosome 17, the breakpoint mapped between KCNJ16 and KCNJ2, and combined with a ~ 5 kb deletion in the 5' of KCNJ2. Based on available capture Hi-C data, the breakpoint on chromosome 17 separated KCNJ2 from a putative enhancer. Gene expression analysis demonstrated downregulation of KCNJ2 in both patient's blood cells and cultured skin fibroblasts. Our findings suggest that a complex rearrangement falling in the 5' of KCNJ2 may mimic the developmental consequences of in tandem duplications affecting the SOX9-KCNJ2/Sox9-Kcnj2 locus. This finding adds weight to the notion of an intricate role of gene regulatory regions and, presumably, the related three-dimensional chromatin structure in normal and abnormal human morphology.
Identifiants
pubmed: 34821995
doi: 10.1007/s00439-021-02403-y
pii: 10.1007/s00439-021-02403-y
doi:
Substances chimiques
KCNJ2 protein, human
0
Potassium Channels, Inwardly Rectifying
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
217-227Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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