Chung-Jansen syndrome can mimic Cornelia de Lange syndrome: Another player among chromatinopathies?

Cornelia de Lange syndrome (CdLS) is a rare multisystem congenital neurodevelopmental disorder (NDD) characterized by distinctive facial anomalies, short stature, developmental delay, hirsutism, gastrointestinal abnormalities and upper limb reduction defects. CdLS syndrome is associated with causative variants in genes encoding for the cohesin complex, a cellular machinery involved in chromatid pairing, DNA repair and gene-expression regulation. In this report, we describe a familial case of a syndromic presentation in a 4-year-old patient (P1) and in his mother (P2). Trio-based Whole Exome Sequencing (WES) performed on P1 was first negative. Since his phenotypic evolution during the follow-up was reminiscent of the CdLS spectrum, a reanalysis of WES data, focused on CdLS-related genes, was requested. Although no alterations in those genes was detected, we identified the likely pathogenetic variant c.40G > A (p.Glu14Lys) in the PHIP gene, in the meanwhile associated with Chung-Jansen syndrome. Reverse phenotyping carried out in both patients confirmed the molecular diagnosis. CHUJANS belongs to NDDs, featuring developmental delay, mild-to-moderate intellectual disability, behavioral problems, obesity and facial dysmorphisms. Moreover, as here described, CHUJANS shows a significant overlap with the CdLS spectrum, with specific regard to facial gestalt. On the basis of our findings, we suggest to include PHIP among genes routinely analyzed in patients belonging to the CdLS spectrum.

Pathogenic PHIP Variants are Variably Associated With CAKUT.

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney disease in children. Although only 20% of cases can be genetically explained, the majority remain without an identified underlying etiology. The neurodevelopmental disorder Chung-Jansen syndrome (CHUJANS) is caused by haploinsufficiency of Pleckstrin homology domain-interacting protein (PHIP) and was previously associated with genital malformations. Anecdotal coincidence of CHUJANS and CAKUT prompted us to investigate whether urorenal malformations are part of the phenotypic spectrum of CHUJANS. Methods: Analysis of existing CHUJANS and CAKUT cohorts, consulting matchmaking platforms, and systematic literature review to look for additional patients with both CHUJANS and CAKUT. Prenatal expression studies in murine and human renal tissues to investigate the role for PHIP in kidney development. Results: We identified 4 novel and 8 published cases, indicating variable expressivity with a urorenogenital trait frequency of 5% to 35%. The prenatal expression studies supported a role for PHIP in normal kidney and urinary tract development. Conclusion: Pathogenic PHIP gene variants should be considered as causative in patients with syndromal CAKUT. Conversely, patients with CHUJANS should be clinically evaluated for urorenogenital manifestations. Because neurodevelopmental disorders are often associated with kidney phenotypes, an interdisciplinary re-evaluation offers promise in identifying incompletely penetrant kidney associations and uncovering novel molecular mechanisms of disturbed nephrogenesis.

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

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.

Chung-Jansen Syndrome with obesity.

Chung-Jansen Syndrome is a recently identified obesity syndrome, characteristic clinical features of which are global developmental delay, intellectual disability, obesity and dysmorphism (DIDOD). We present a child with the syndrome who also had hypothyroidism and renal involvement in form of small kidneys on one side. The next generation sequencing done in the child showed a nonsense variant in the PHIP gene leading to premature chain termination in the protein on bioinformatic analysis.