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Goldberg–Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP
Author(s) -
MacKenzie Katherine C.,
Graaf Bianca M.,
Syrimis Andreas,
Zhao Yuying,
Brosens Erwin,
Mancini Grazia M. S.,
Schot Rachel,
Halley Dicky,
Wilke Martina,
Vøllo Arve,
Flinter Frances,
Green Andrew,
Mansour Sahar,
Pilch Jacek,
Stark Zornitza,
ZambaPapanicolaou Eleni,
ChristophidouAnastasiadou Violetta,
Hofstra Robert M. W.,
Jongbloed Jan D. H.,
Nicolaou Nayia,
Tanteles George A.,
Brooks Alice S.,
Alves Maria M.
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24097
Subject(s) - missense mutation , biology , phenotype , single nucleotide polymorphism , nonsense , genetics , nonsense mediated decay , gene , loss function , genotype , genotype phenotype distinction , rna , rna splicing
Abstract Goldberg–Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene ( KIFBP ). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP : seven with nonsense variants and two with missense variants. To our knowledge, this is the first time that missense variants have been reported in GOSHS. We functionally investigated the effect of the variants identified, in an attempt to find a genotype–phenotype correlation. We also determined whether common Hirschsprung disease (HSCR)‐associated single nucleotide polymorphisms (SNPs), could explain the presence of HSCR in GOSHS. Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein. However, no correlation was found between the severity of GOSHS and the location of the variants. We were also unable to find a correlation between common HSCR‐associated SNPs, and HSCR development in GOSHS. In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease.

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