Gabriele-De Vries Syndrome

Clinical characteristics.

Gabriele-de Vries syndrome is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals and a wide spectrum of functional and morphologic abnormalities. Intrauterine growth restriction or low birth weight and feeding difficulties are common. Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies have also been reported. About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities. Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder.

Diagnosis/testing.

The diagnosis of Gabriele-de Vries syndrome is established in a proband by the identification of a heterozygous pathogenic variant involving YY1 or a heterozygous deletion of 14q32.2 involving only YY1.

Management.

Treatment of manifestations: Developmental delay / intellectual disability, craniofacial anomalies (Pierre Robin sequence, cleft palate, craniosynostosis, abnormalities of the lacrimal duct), feeding difficulties, gastroesophageal reflux, constipation, seizures, behavioral manifestations, strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice.

Surveillance: Of clinical manifestations as clinically indicated.

Genetic counseling.

Gabriele-de Vries syndrome is inherited in an autosomal dominant manner. All probands reported to date with Gabriele-de Vries syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a de novo YY1 pathogenic variant or deletion. Risk to future pregnancies is presumed to be low as the proband most likely has a de novo YY1 pathogenic variant or deletion; however, given the theoretic possibility of parental germline mosaicism, recurrence risk to sibs is estimated at 1%, and thus prenatal and preimplantation genetic testing may be considered.

Suggestive Findings

The clinical spectrum of Gabriele-de Vries syndrome is variable. Gabriele-de Vries syndrome should be considered in individuals presenting with the following clinical findings.

Clinical findings

• Mild-to-profound developmental delay and/or intellectual disability; AND
• Any of the following features presenting in infancy or childhood:
  • Craniofacial dysmorphisms (see Clinical Description)
  • Intrauterine growth restriction / low birth weight
  • Feeding difficulties
  • Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
  • Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
  • Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (see Clinical Description)

Establishing the Diagnosis

The diagnosis of Gabriele-de Vries syndrome is established in a proband who has one of the following on molecular genetic testing (see Table 1):

• A heterozygous pathogenic variant involving YY1
• A heterozygous deletion of 14q32.2 involving YY1 only

Note: See Genetically Related Disorders for information about deletions of 14q32.2 that involve YY1 and other, adjacent genes.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis ofYY1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including YY1) that cannot be detected by sequence analysis.
  Note: To date, most individuals with a YY1 deletion have been identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder; however, many CMA platforms do not include sufficient coverage for this region and thus a YY1 deletion may not be detected.
• An intellectual disability (ID) multigene panel that includes YY1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a non-diagnostic CMA at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of YY1, some panels for ID may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder an ID multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Exome sequencing, which does not require the clinician to determine which gene is likely involved, yields results similar to an ID multigene panel but has two advantages: (1) a multigene panel may not include all rare genes recently identified as causing ID; and (2) exome sequencing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.
  If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Evaluations and Referrals Following Initial Diagnosis

Evaluation by a multidisciplinary team can be beneficial.

To establish the extent of disease and needs in an individual diagnosed with Gabriele-de Vries syndrome, the evaluations summarized Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis.

Treatment of Manifestations

Surveillance

A developmental pediatrician or a geneticist should coordinate the follow up of a child with Gabriele-de Vries syndrome. Surveillance of gastrointestinal, craniofacial, cardiac, renal, genital, skeletal, and endocrine abnormalities should be tailored to the affected individual according to the specific problems identified at diagnosis.

Long-term follow up by other specialists is also recommended and includes the following.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.