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.

Keywords: CHUJANS; CUL4B; Chung-Jansen syndrome; DD; DIDOD syndrome; ID; PHIP; obesity.

FIGURE 1

PHIP variants associated with Chung-Jansen syndrome identified in the present cohort and/or described in the literature (A) Schematic representation of PHIP exons (top; 1–40) and its encoded protein (bottom) showing the identified variants relative to the protein domains/regions. Variants identified in the present cohort are shown above, and the described in the literature are shown below. Variants are labelled with the nomenclature based on changes at protein levels except for splicing variants, for which coding DNA sequence nomenclature was used (B) Schematic representation of the deletions encompassing the PHIP gene (blue) identified in the present cohort (red) and in the literature (light red). Deletion sizes are shown. White arrows identify the direction of PHIP transcription. Genes in dark grey are, as PHIP, OMIM morbid genes (C) Comparison of the distribution of the PHIP variants identified in the present cohort and/or in the literature with the variants reported in gnomAD. Number of individuals with gnomAD variants were plotted for each combined codon. gnomAD variants were stratified by damage potential (based on variant type and CADD score).

FIGURE 2

Summary of the main clinical features associated with PHIP variants (A) Summary of the most frequent clinical features of our cohort expressed as a percentage (n = 23) (B) Summary of the most frequent craniofacial dysmorphism of our cohort expressed as a percentage (n = 23) (C) Age of onset of overweight/obesity and the cumulative frequency expressed as a percentage.

FIGURE 3

Facial appearance of the individuals of our cohort (A) Individual 1 (10 years) (B,C) individual 2 (1 year, 12 years) (D,E) individual 4 (3 years, 6 years) (F–H) individual 5 (3 years, 12 years, profile 12 years) (I,J) individual 6 (16 years) (K) individual 7 (49 years) (L) individual 8 (11 years) (M,N) individual 10 (39 years) (O) individual 11 (7 years) (P,Q) individual 13 (38 years) (R,S) individual 15 (37 years) (T) individual 16 (16 years) (U) individual 17 (41 years) (V) individual 18 (age unknown) (W) individual 19 (age unknown) (X,Y) individual 20 (16 years) (Z,AA) individual 21 (10 years) (BB) individual 22 (16 years) (CC) individual 23 (9 years).

FIGURE 4

Pictures of individuals showing hand and/or feet anomalies (A) Hands of individual 1 (10 years) (B) hands of individual 2 (12 years) (C) hands of individual 6 (16 years) (D) feet of individual 1 (10 years) (E) feet of individual 17 (41 years).

FIGURE 5

Analysis of the facial Gestalt with Gestaltmatcher. (A) tSNE analysis to validate whether PHIP individuals cluster based on the type of mutations (missense, loss-of-function, splice site). (B) tSNE analysis of patients with PHIP alteration, CUL4B alteration or PWS, which shows a clear phenotypic separation of the three conditions. (C) Average faces for healthy controls and each of the differential clinical diagnoses for CHUJANS, namely CUL4B-related disorders and PWS.