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

Abstract

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.

Clinical phenotypes of individuals with Chung–Jansen syndrome across age groups

“…Compared to the previous studies (Table 4), we found comparable results with developmental delay in 85% (Jansen et al, 2018; Kampmeier et al, 2022). Our cohort had no report of developmental regression.…”

“…We started to observe obesity/overweight at the age of seven, and the frequency of obesity/overweight increases with age. Kampmeier et al (2022) found that the incidence of obesity/overweight rose sharply during puberty. However, Kampmeier et al also found that some individuals as young as 5 years old were already obese/overweight.…”

Computational facial analysis for rare Mendelian disorders

“…There were no clear clusters for each type of variant. This figure was published in the original paper (Kampmeier et al, 2023) as Figure 5.…”

“…The same concept of similarity measurement can also be applied to compare different disorders. Kampmeier et al utilized tSNE to visualize the clustering among the patients with PHIP, CUL4B , and Prader‐Willi syndrome (PWS; OMIM #176270) in two‐dimensional space (Kampmeier et al, 2023). The tSNE plot showed that three groups formed three clusters, although some CUL4B patients were similar to PWS patients.…”

Facilitating the Molecular Diagnosis of Rare Genetic Disorders Through Facial Phenotypic Scores

“…With the recent advances in computer vision, many AI‐based applications have begun to be used to facilitate diagnosis through facial image analysis (Dingemans et al., 2022; Dudding‐Byth et al., 2017; Gurovich et al., 2019; Hsieh et al., 2022; Hustinx et al., 2023; Porras et al., 2021; Sümer et al., 2023) and to further delineate the phenotypes of novel diseases (Aerden et al., 2023; Asif et al., 2022; Averdunk et al., 2023; Ebstein et al., 2023; Guo et al., 2022; Kampmeier et al., 2022; Knaus et al., 2018; Lyon et al., 2023; Marbach et al., 2019; Oppermann et al., 2023; Pantel et al., 2018).…”