Popov-Chang Syndrome

A number sign (#) is used with this entry because of evidence that Popov-Chang syndrome (POPCHAS) is caused by heterozygous mutation in the YWHAZ gene (601288) on chromosome 8q22.

Description

Popov-Chang syndrome (POPCHAS) is a neurodevelopmental disorder characterized by global developmental delay apparent from infancy. Affected individuals have impaired intellectual development and poor or absent speech, as well as behavioral abnormalities. Most patients have significant facial dysmorphism, including coarse features, frontal bossing, and abnormal eye shape. Additional features are highly variable and can include seizures, short stature, feeding difficulties, and skin abnormalities (summary by Popov et al., 2019).

Clinical Features

Popov et al. (2019) reported 5 unrelated patients, ranging in age from 9 to 17 years, with variable manifestations of a neurodevelopmental disorder. All had global developmental delay, with mildly delayed walking ability, impaired intellectual development (IQ of 1 patient was 55), and poor or absent speech. Three had significant behavioral abnormalities, including autistic-like behavior, self-injurious behavior, fear of social interaction, and poor concentration. One patient had episodic hyperventilation associated with stressful situations. Three patients had seizures in childhood that remitted or could be controlled. Brain imaging tended to be normal, although one showed nonspecific cerebellar hypoplasia and cerebral atrophy. Four patients had notable but variable dysmorphic features, including frontal bossing, coarse facies, triangular face, ptosis, thin upper lip, thick lips, proptosis, long philtrum, and coarse hair. Photographs of the patients (figure 1) suggested abnormal eye shape, depressed nasal bridge with upturned tip, long nose, and mild hypertelorism. The photograph of patient 3 indicated milder dysmorphic features. A few patients had additional features, including poor feeding, short stature, poor growth, small hands and feet, and fifth finger clinodactyly. One patient (patient 1) had pulmonic stenosis, hydrocephalus, recurrent otitis media, hypogammaglobulinemia, lymphopenia, hyperkeratosis pilaris with dry skin, scoliosis, and hypertension, indicating a systemic disorder. None of the other 4 patients had cardiac malformations or skin involvement. One patient had cataracts and retinopathy.

Molecular Genetics

In 5 unrelated patients with POPCHAS, Popov et al. (2019) identified 5 different de novo heterozygous mutations in the YWHAZ gene (601288.0001-601288.0005), including 3 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. The first patient was identified through a genome sequencing research study, and the other 4 patients were subsequently identified through GeneMatcher or through data-sharing of exome sequencing. Detailed functional studies of 1 of the missense variants (S230W; 601288.0001) in Xenopus indicated that this mutation resulted in a gain-of-function effect with increased activity of the Ras-Erk signaling pathway (see ANIMAL MODEL). Functional studies of the other variants and studies of patient cells were not performed.

Animal Model

Popov et al. (2019) found that injection of the S230W mutation into Xenopus embryos caused dark pigmentation, possibly reflecting changes in cell shape, as well as defects in head structure and shortened and bent body axis compared to controls. The abnormalities induced by the mutant gene were more severe than those induced by overexpression of the wildtype gene. Further studies showed that the mutant YWHAZ protein was able to rescue defects induced by dominant-negative FGFR1 (136350) and stimulated Raf-dependent Erk phosphorylation more efficiently than wildtype, consistent with a gain of function.