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
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 [1,2,11-14]. Here, we report on a novel missense variant of
This study was approved by the Institutional Review Board (IRB) of Hanyang University Medical Center, Seoul, Korea (IRB No. 2019-11-040). Informed consent was obtained from both parents of the participant. WES was performed in 3billion Inc. (Seoul, Korea) using genomic DNA isolated from the patient’s whole blood. All exons from the entire human genome (approximately 22,000) were captured using an xGen Exome Research Panel v2 (Integrated DNA Technologies Inc., Coralville, IA, USA). The captured genomic regions were sequenced using a NovaSeq 6000 (Illumina Inc., San Diego, CA, USA). Raw genome sequencing data analyses included alignment to the reference sequence (National Center for Biotechnology Information genome assembly GRCh37; accessed in February of 2009). The mean depth of coverage was 100-fold with 99.2% coverage. Variant calling, annotation, and prioritization were performed as previously described . Developmental delay and facial dysmorphism served as filtering indices for clinical symptoms to analyze the candidate variants.
A 7-month-old girl visited the outpatient clinic for children because of developmental delay. The patient was born at 39+5 gestational weeks with a body weight of 3,140 g (–0.15 standard deviation [SD]) at birth. She was the only child of non-consanguineous, healthy Korean parents with no family history of developmental delays or multiple congenital abnormalities. Prenatal examinations did not reveal any abnormalities. She presented a mild dysmorphic facial appearance including facial asymmetry, micrognathia, and low-set ears. The girl’s height was 71.2 cm (1.7 SD), weight was 8.5 kg (0.9 SD), and head circumference was 43 cm (0.2 SD). She showed no apparent neurological abnormalities, such as change in muscular tone, increased deep tendon reflexes, or pathologic reflexes. Results of laboratory tests, including blood chemistry and endocrine tests as well as the results of tandem mass spectrometry screening of inborn errors of metabolism were normal. Results of abdominal ultrasound, echocardiography, skeletal survey, and brain magnetic resonance imaging at the age of 9 months were also normal. Audiometry revealed a mild sensorineural hearing loss in the right ear. An assessment using the Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-III) at the age of 7 months demonstrated a mild degree of global developmental delay, especially in gross motor function.
To explore the possibility of a genetic syndrome, we performed genetic tests, such as chromosomal microarray and WES, to identify the underlying genetic defect. Chromosomal microarray revealed a normal karyotype of 46, XX, without copy number variation. WES identified a novel heterozygous missense variant of c.1220C>T (p.His407Arg) in the
Currently, the patient is undergoing various rehabilitation treatments twice a week, such as occupational therapy, neurodevelopment treatment, and activities of daily living.
GADEVS, also known as YY1 haploinsufficiency syndrome, was first reported in 2017 by Gabriele et al. . Since
Phenotypical features of GADEVS include cognitive impairment, behavioral alteration, intrauterine growth restriction, feeding problems, various congenital malformations, and movement disorders . Developmental delay was found in both motor function and speech, and a mild to profound degree of intellectual disability was presented in patients with pathogenic
We identified a de novo missense variant of YY1, which was classified to be likely pathogenic, in an infant with mild developmental delay and subtle facial dysmorphism. Through this case, we expect to expand the clinical and genetic spectra of GADEVS that might be an unidentified cause of syndromic features with developmental delay and facial dysmorphism.
The authors declare that they do not have any conflicts of interest.
This work was supported by Hanyang Medicine-Engineering-Biology Center. The analysis of whole exome sequencing was supported by 3billion Inc. (Seoul, Korea).
Conception and design: JK. Acquisition of data: SB, JHA, HKP, JK. Analysis and interpretation of data: SB, JK. Drafting the article: SB, AY, JK. Critical revision of the article: SB, AY, JK. Final approval of the version to be published: All authors.
Details of the variant identified in the
|Variant type||Missense variant|
aThe pathogenicity of missense variant was predicted using rare exome variant ensemble learner (REVEL) method. bVariant classification is based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.
GnomAD, The Genome Aggregation Database; REVEL, rare exome variant ensemble learner.
Data from the article of Ioannidis NM et al. (Am J Hum Genet 2016;99: 877-85) .