Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele‐de Vries syndrome)

Abstract

YY1 mutations cause Gabriele‐de Vries syndrome, a recently described condition involving cognitive impairment, facial dysmorphism and intrauterine growth restriction. Movement disorders were reported in 5/10 cases of the original series, but no detailed description was provided. Here we present a 21‐year‐old woman with a mild intellectual deficit, facial dysmorphism and a complex movement disorder including an action tremor, cerebellar ataxia, dystonia, and partial ocular apraxia as the presenting and most striking feature. Whole‐exome sequencing revealed a novel heterozygous de novo mutation in YY1 [NM: 003403.4 (YY1): c.907 T > C; p.(Cys303Arg)], classified as pathogenic according to the ACMG guidelines.

Identification of a likely pathogenic variant of YY1 in a patient with developmental delay

“…Furthermore, the targets differentially regulated by YY1 include several genes associated with neurodevelopmental disorders, such as GTF2I, KANSL1, NRXN2, MED12, NSD1, ZBTB20, and HCFC1 [1,7]. Genotypes of GADEVS include five truncating mutations, eight mutations resulting in a missense change, or 13 deletions of YY1 and other neighboring genes [1,2,12,13]. In the current study, the missense variant is located in the ultimate exon, where most of the pathogenic variants have been described [1,13].…”

“…GADEVS, also known as YY1 haploinsufficiency syndrome, was first reported in 2017 by Gabriele et al [1]. Since YY1 was considered a candidate gene for syndromic intellectual disability with intrauterine growth retardation and dysmorphic facial appearance on the basis of trio exome sequencing conducted by Vissers et al, 26 cases have been reported [1,2,[11][12][13]. YY1 is a zinc finger containing multifunctional transcription factor that regulates transcriptional activation and repression in nervous systems [3].…”

“…Thus far, she has not shown feeding difficulties or other neurologic symptoms. However, regular evaluation of neurologic disorders is required because many neurologic symptoms, including movement disorders, are presented by patients aged >10 years [1,2].…”

“…Gabriel-de Vries syndrome (GADEVS, MIM #617557) is a newly defined genetic syndrome characterized by developmental delay, craniofacial dysmorphism, intrauterine growth retardation, and other neurologic manifestations [1,2]. This neurodevelopmental disorder resulted from an aberration of the YY1 gene (MIM #600013) located on chromosome 14q32.2, which encodes the Yin Yang 1 protein that plays a crucial role in neuronal development and neuroendocrine malignancy [3][4][5].…”

“…Because next generation sequencing techniques, including chromosomal microarray and whole exome sequencing (WES), enables successful identification of various genomic variants in undiagnosed syndromic cases with developmental delay in a time-and cost-effective manner, the importance of exome sequencing for identifying the genetic etiology is gradually being emphasized [9,10]. Based on the data from multiple studies and the Deciphering Developmental Disorders Study database, more than 100 sequence and copy number variants of YY1 have been identified among patients with syndromic developmental delay [1,2,[11][12][13][14]. Here, we report on a novel missense variant of YY1, identified by WES, in an infant with a developmental delay.…”