Jansen-De Vries Syndrome

A number sign (#) is used with this entry because of evidence that Jansen-de Vries syndrome (JDVS) is caused by heterozygous mutation in the PPM1D gene (605100) on chromosome 17q23.

Description

Jansen-de Vries syndrome (JDVS) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with speech delay, and behavioral abnormalities. Most patients have variable additional features, including feeding and gastrointestinal difficulties, high pain threshold and/or hypersensitivity to sound, and dysmorphic features, including mild facial abnormalities, strabismus, and small hands and feet (summary by Jansen et al., 2017).

Clinical Features

Jansen et al. (2017) reported 14 unrelated patients, ranging in age from 2 to 21 years, with a neurodevelopmental disorder with common, although slightly variable, additional features. All but 1 patient had mild to severe intellectual disability, often with speech delay, and 11 (79%) had behavioral problems, such as anxiety disorders, attention deficit-hyperactivity disorder (ADHD), obsessive behavior, sensory integration problems, and autism spectrum disorder (ASD). The 1 patient with a normal IQ of 96 had learning difficulties, an anxiety disorder, and attention problems. Ten patients (71%) had some type of gastrointestinal difficulty, including feeding difficulties, periods of vomiting with or without fever, constipation, and gastroesophageal reflux. Nine patients had a high pain threshold and 7 were hypersensitive to sound. Ten patients had small hands, often with brachydactyly, and several had short stature. Other common features included hypotonia, broad-based gait, and visual problems, such as myopia, hypermetropia, and strabismus. Most patients had dysmorphic facial features, although these features varied: common findings included broad forehead, low-set posteriorly rotated ears, upturned nose, and broad mouth with thin upper lip.

Inheritance

Jansen et al. (2017) demonstrated that Jansen-de Vries syndrome is an autosomal dominant disorder.

Molecular Genetics

In 14 unrelated patients with JDVS, Jansen et al. (2017) identified heterozygous truncating mutations in the PPM1D gene (see, e.g., 605100.0001-605100.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were shown to occur de novo, except in 1 case in which parental DNA was not available for analysis. All mutations were located in the last or penultimate exon (exons 5 and 6) and were predicted to escape nonsense-mediated mRNA decay, resulting in a truncated protein that would retain the functional phosphatase domain but lack the nuclear localization signal. Analysis of cells from several patients showed that the mutations resulted in stable truncated transcripts. Patient cells showed normal p53 (TP53; 191170) activation in response to ionizing radiation, but there was a cell-growth disadvantage, suggesting a possible effect of the mutation on the stress-response pathway. The findings pointed to a role of cell-cycle checkpoint genes in neurodevelopmental disorders.