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author Kampmeier, Antje
Leitão, Elsa
Parenti, Ilaria
Beygo, Jasmin
Depienne, Christel
Bramswig, Nuria C
Hsieh, Tzung-Chien
Afenjar, Alexandra
Beck-Wödl, Stefanie
Grasshoff, Ute
Haack, Tobias B
Bijlsma, Emilia K
Ruivenkamp, Claudia
Lausberg, Eva
Elbracht, Miriam
Haanpää, Maria K
Koillinen, Hannele
Heinrich, Uwe
Rost, Imma
Jamra, Rami Abou
Popp, Denny
Koch-Hogrebe, Margarete
Rostasy, Kevin
López-González, Vanesa
Sanchez-Soler, María José
Macedo, Catarina
Schmetz, Ariane
Steinborn, Carmen
Weidensee, Sabine
Lesmann, Hellen
Marbach, Felix
Caro, Pilar
Schaaf, Christian P.
Krawitz, Peter
Wieczorek, Dagmar
Kaiser, Frank J
Kuechler, Alma
author_facet Kampmeier, Antje
Leitão, Elsa
Parenti, Ilaria
Beygo, Jasmin
Depienne, Christel
Bramswig, Nuria C
Hsieh, Tzung-Chien
Afenjar, Alexandra
Beck-Wödl, Stefanie
Grasshoff, Ute
Haack, Tobias B
Bijlsma, Emilia K
Ruivenkamp, Claudia
Lausberg, Eva
Elbracht, Miriam
Haanpää, Maria K
Koillinen, Hannele
Heinrich, Uwe
Rost, Imma
Jamra, Rami Abou
Popp, Denny
Koch-Hogrebe, Margarete
Rostasy, Kevin
López-González, Vanesa
Sanchez-Soler, María José
Macedo, Catarina
Schmetz, Ariane
Steinborn, Carmen
Weidensee, Sabine
Lesmann, Hellen
Marbach, Felix
Caro, Pilar
Schaaf, Christian P.
Krawitz, Peter
Wieczorek, Dagmar
Kaiser, Frank J
Kuechler, Alma
author_sort Kampmeier, Antje
collection PubMed
description 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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spelling pubmed-98861392023-01-31 PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals Kampmeier, Antje Leitão, Elsa Parenti, Ilaria Beygo, Jasmin Depienne, Christel Bramswig, Nuria C Hsieh, Tzung-Chien Afenjar, Alexandra Beck-Wödl, Stefanie Grasshoff, Ute Haack, Tobias B Bijlsma, Emilia K Ruivenkamp, Claudia Lausberg, Eva Elbracht, Miriam Haanpää, Maria K Koillinen, Hannele Heinrich, Uwe Rost, Imma Jamra, Rami Abou Popp, Denny Koch-Hogrebe, Margarete Rostasy, Kevin López-González, Vanesa Sanchez-Soler, María José Macedo, Catarina Schmetz, Ariane Steinborn, Carmen Weidensee, Sabine Lesmann, Hellen Marbach, Felix Caro, Pilar Schaaf, Christian P. Krawitz, Peter Wieczorek, Dagmar Kaiser, Frank J Kuechler, Alma Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2023-01-16 /pmc/articles/PMC9886139/ /pubmed/36726590 http://dx.doi.org/10.3389/fcell.2022.1020609 Text en Copyright © 2023 Kampmeier, Leitão, Parenti, Beygo, Depienne, Bramswig, Hsieh, Afenjar, Beck-Wödl, Grasshoff, Haack, Bijlsma, Ruivenkamp, Lausberg, Elbracht, Haanpää, Koillinen, Heinrich, Rost, Jamra, Popp, Koch-Hogrebe, Rostasy, López-González, Sanchez-Soler, Macedo, Schmetz, Steinborn, Weidensee, Lesmann, Marbach, Caro, Schaaf, Krawitz, Wieczorek, Kaiser and Kuechler. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Kampmeier, Antje
Leitão, Elsa
Parenti, Ilaria
Beygo, Jasmin
Depienne, Christel
Bramswig, Nuria C
Hsieh, Tzung-Chien
Afenjar, Alexandra
Beck-Wödl, Stefanie
Grasshoff, Ute
Haack, Tobias B
Bijlsma, Emilia K
Ruivenkamp, Claudia
Lausberg, Eva
Elbracht, Miriam
Haanpää, Maria K
Koillinen, Hannele
Heinrich, Uwe
Rost, Imma
Jamra, Rami Abou
Popp, Denny
Koch-Hogrebe, Margarete
Rostasy, Kevin
López-González, Vanesa
Sanchez-Soler, María José
Macedo, Catarina
Schmetz, Ariane
Steinborn, Carmen
Weidensee, Sabine
Lesmann, Hellen
Marbach, Felix
Caro, Pilar
Schaaf, Christian P.
Krawitz, Peter
Wieczorek, Dagmar
Kaiser, Frank J
Kuechler, Alma
PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals
title PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals
title_full PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals
title_fullStr PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals
title_full_unstemmed PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals
title_short PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals
title_sort phip-associated chung-jansen syndrome: report of 23 new individuals
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9886139/
https://www.ncbi.nlm.nih.gov/pubmed/36726590
http://dx.doi.org/10.3389/fcell.2022.1020609
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