<i>PHIP</i> variants associated with Chung–Jansen syndrome disrupt replication fork stability and genome integrity

Tirado-Class, Neysha; Hathaway, Caitlin; Chung, Wendy K.; Dungrawala, Huzefa

doi:10.1101/mcs.a006212

Cited by 2 publications

(2 citation statements)

References 29 publications

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“…Because of possible overlapping facial features, we compared the facial gestalt of individuals with variants affecting PHIP with the facial gestalt of published individuals with CUL4B alterations. Since PHIP/ DCAF14 is one of the multiple substrate receptors of the proteolytic CUL4-DDB1 (Jansen et al, 2018;Tirado-Class et al, 2022), we postulated a phenotypic overlap between patients with PHIP or CUL4B variants. Furthermore, both proteins are involved in fork stability and genome integrity (Tirado-Class et al, 2022).…”

Section: Facial Gestaltmentioning

confidence: 98%

“…Since PHIP/ DCAF14 is one of the multiple substrate receptors of the proteolytic CUL4-DDB1 (Jansen et al, 2018;Tirado-Class et al, 2022), we postulated a phenotypic overlap between patients with PHIP or CUL4B variants. Furthermore, both proteins are involved in fork stability and genome integrity (Tirado-Class et al, 2022). GestaltMatcher did not confirm this hypothesis and rather showed that each disorder shows its distinct characteristic facial phenotype.…”

Section: Facial Gestaltmentioning

confidence: 98%

See 1 more Smart Citation

PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals

Kampmeier

Leitão

Parenti

et al. 2023

Front. Cell Dev. Biol.

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In 2016 and 2018, Chung, Jansen and others described a new syndrome caused by haploinsufficiency of PHIP (pleckstrin homology domain interacting protein, OMIM *612,870) and mainly characterized by developmental delay (DD), learning difficulties/intellectual disability (ID), behavioral abnormalities, facial dysmorphism and obesity (CHUJANS, OMIM #617991). So far, PHIP alterations appear to be a rare cause of DD/ID. “Omics” technologies such as exome sequencing or array analyses have led to the identification of distinct types of alterations of PHIP, including, truncating variants, missense substitutions, splice variants and large deletions encompassing portions of the gene or the entire gene as well as adjacent genomic regions. We collected clinical and genetic data of 23 individuals with PHIP-associated Chung-Jansen syndrome (CHUJANS) from all over Europe. Follow-up investigations (e.g. Sanger sequencing, qPCR or Fluorescence-in-situ-Hybridization) and segregation analysis showed either de novo occurrence or inheritance from an also (mildly) affected parent. In accordance with previously described patients, almost all individuals reported here show developmental delay (22/23), learning disability or ID (22/23), behavioral abnormalities (20/23), weight problems (13/23) and characteristic craniofacial features (i.e. large ears/earlobes, prominent eyebrows, anteverted nares and long philtrum (23/23)). To further investigate the facial gestalt of individuals with CHUJANS, we performed facial analysis using the GestaltMatcher approach. By this, we could establish that PHIP patients are indistinguishable based on the type of PHIP alteration (e.g. missense, loss-of-function, splice site) but show a significant difference to the average face of healthy individuals as well as to individuals with Prader-Willi syndrome (PWS, OMIM #176270) or with a CUL4B-alteration (Intellectual developmental disorder, X-linked, syndromic, Cabezas type, OMIM #300354). Our findings expand the mutational and clinical spectrum of CHUJANS. We discuss the molecular and clinical features in comparison to the published individuals. The fact that some variants were inherited from a mildly affected parent further illustrates the variability of the associated phenotype and outlines the importance of a thorough clinical evaluation combined with genetic analyses for accurate diagnosis and counselling.

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Section: Facial Gestaltmentioning

confidence: 98%