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 (or likely pathogenic) variant involving YY1
• A heterozygous deletion of 14q32.2 involving YY1 only

Note: (1) See Genetically Related Disorders for information about deletions of 14q32.2 that involve YY1 and other, adjacent genes. (2) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

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 nondiagnostic CMA 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.

Clinical Description

To date, ten individuals with a de novo pathogenic YY1 variant have been described with an overlapping phenotype [Vissers et al 2010, Gabriele et al 2017]. De novo YY1 variants result in syndromic ID with a wide spectrum of functional and morphologic abnormalities, in particular intrauterine growth restriction or low birth weight, feeding difficulties, congenital anomalies, nonspecific craniofacial dysmorphism, and neurologic and behavioral abnormalities.

Developmental delay (DD) and intellectual disability (ID). All individuals with a YY1 intragenic pathogenic variant had DD/ID, which was usually mild (IQ 50-70) to moderate (IQ 35-49). One individual with a de novo YY1 pathogenic variant manifested severe ID.

• Gross motor skills. The majority of individuals with a de novo YY1 pathogenic variant (8/10) had motor delay and started walking independently between age 15 months and 6.5 years (median age: 2 years). Three affected individuals sat alone at 12 months. Gait disturbances were noticed in two affected individuals, specifically toe walking and waddling gait.
• Language development was delayed in half of the children with a pathogenic YY1 variant (5/10). Severity varied between individuals; while two children had mild speech delay, one child used two- to three-word sentences at age seven years and another child, age nine years, did not use verbal communication.

Craniofacial features. All individuals described have facial dysmorphisms. The facial gestalt in most of the individuals with a de novo YY1 variant includes the following:

• Generalized facial asymmetry, with mild discrepancy in the size of one side of the face compared to the other
• Broad forehead
• Fullness of upper eyelids
• Downslanted palpebral fissures
• Bulbous nose
• Malar flattening
• Indentation of the vermilion of the upper lip resembling a ginkgo leaf
• Thick vermilion of the lower lip
• Pointed chin

External ear malformations are common and include the following:

• Abnormally shaped ears
• Simple ears
• Posteriorly rotated ears
• Low-set ears
• Protruding ears

Rare craniofacial findings have included the following:

• Abnormalities of the lacrimal duct, specifically lacrimal duct stenosis and hypoplastic lacrimal duct
• Craniosynostosis in one affected individual (suture not specified)
• Pierre Robin sequence with a cleft palate in one affected individual

Growth. Low birth weight was reported in approximately half of newborns with a YY1 pathogenic variant (5/9). Later weight was recovered and only two of these individuals maintained persistently low body weight. Short stature was observed in two affected individuals with a pathogenic YY1 variant.

Feeding difficulties / gastrointestinal abnormalities. Feeding difficulties occurred often. Oral-pharyngeal dysphagia with chewing and swallowing difficulty may be seen and some individuals require G-tube insertion for feeding problems.

Neurologic abnormalities. About half of affected individuals had neurologic problems, including hypotonia, abnormalities of movement (1 affected individual with tremor and 2 with progressive dystonia, including torsion dystonia), gait abnormalities, and, rarely, febrile seizures.

Behavioral phenotype. Approximately half of the individuals with a pathogenic YY1 variant had behavioral problems (5/9), which included attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder. Sleeping problems were described in a minority of affected individuals (2/9).

Neuroimaging abnormalities. A variety of nonspecific morphologic abnormalities of the central nervous system (CNS) have been described, including the following:

• Abnormalities of the subarachnoid space (widened subarachnoid space)
• Delayed myelination
• Frontal gliosis
• Cortical dysplasia
• Focal areas of encephalomalacia
• Unilateral and/or bilateral dilatation of the lateral ventricles
• Abnormalities of cerebral white matter (cerebral white matter atrophy, subcortical bifrontal white matter foci)
• Abnormalities of the corpus callosum (ranging from hypoplasia of the corpus callosum to agenesis of corpus callosum)

Each of the reported CNS morphologic abnormalities was observed in one or two individuals (occurring alone or concomitantly with another neuroimaging abnormality) and is not exclusive to Gabriele-de Vries syndrome.

Congenital anomalies. A variety of structural malformations have been described:

• Eye abnormalities. Strabismus and abnormalities of refraction (hypermetropia and astigmatism) were present in more than half of affected individuals.
• Heart abnormalities. Patent foramen ovale and small aorto-pulmonary collateral has been described in one individual and Ebstein's anomaly of the tricuspid valve in another.
• Renal abnormalities. Hydronephrosis (2/7), occurring concomitantly or not with ureteropelvic junction stenosis (1/7), was reported in a minority of affected individuals.
• Genital abnormalities. Bilateral cryptorchidism was unusual, being reported in only one individual (1/5).
• Skeletal abnormalities. The majority of affected individuals manifested abnormalities of the extremities, which varied greatly in location and severity. The following anomalies were present in no more than one individual each:
  • Unilateral hemihypotrophy of lower limb
  • Patella luxations
  • Increased laxity of fingers
  • Long fingers
  • Sydney crease *
  • Sandal gap
  • Hallux valgus
  • Distal arthrogryposis

* Note: The Sydney crease is a proximal transverse (5-finger) crease that starts on the radial side of the hand near the base of the index finger and extends completely to the ulnar margin of the palm.

Endocrine abnormalities were reported in three affected individuals and included hypothyroidism in two and growth hormone deficiency in one.

Other. The following features have been observed in one affected individual each, and therefore it is unclear if the finding is related to the diagnosis of Gabriele-de Vries syndrome or is a coincidental finding:

• Recurrent infections
• Breast hypoplasia
• Hyperextensible skin
• Childhood-onset neuroblastoma

Genotype-Phenotype Correlations

Given the small number of affected individuals reported in the literature, no genotype-phenotype correlations are currently known.

Prevalence

Gabriele-de Vries syndrome is a rare condition. So far, ten affected individuals worldwide have been described in the medical literature with a de novo intragenic YY1 variant.

The prevalence of Gabriele-de Vries syndrome is yet to be determined. To date, de novo pathogenic variants in YY1 were identified in 0.03%-1% of individuals with unexplained intellectual disability in diverse studied cohorts with estimates of prevalence varying in different subsets of individuals tested [Vissers et al 2010, Gabriele et al 2017].

Since individuals have been recruited via large exome sequencing projects, it is expected that more affected individuals will be diagnosed with Gabriele-de Vries syndrome as the use of genomic testing increases.

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.

Mode of Inheritance

Gabriele-de Vries syndrome is inherited in an autosomal dominant manner and is typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• 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.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the YY1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of germline mosaicism have been reported to date.
• Theoretically, if the parent is the individual in whom the YY1 pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the YY1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Individuals with Gabriele-de Vries syndrome are not known to reproduce.

Other family members. Given that all probands with Gabriele-de Vries syndrome reported to date have the disorder as a result of a de novo YY1 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo YY1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Cancer and Benign Tumors

YY1 is overexpressed in several sporadic tumors including hepatocellular carcinoma [Zhang et al 2012], breast, ovarian, brain, prostate, colon, and esophagus tumors, as well as osteosarcoma and melanoma, as recently extensively reviewed [Khachigian 2018]. Its upregulation is correlated with poor prognosis [Zaravinos & Spandidos 2010, Cho & Bonavida 2017, Khachigian 2018]. Moreover, variants in threonine 372 (p.Thr372Arg), which increase its transcriptional activity, have been associated with the onset of sporadic insulinomas [Cao et al 2013, Lichtenauer et al 2015]. Consistent with the pleiotropic and exquisitely context-dependent aspects of its function, YY1 has also been found to promote the expression of tumor suppressors such as BRCA1 and p21 [Khachigian 2018].

Author Notes

The authors also recommend the following resource: Human Disease Genes Website Series: YY1.

To gain further insight, and expand the clinical phenotype of pathogenic variants within the complete coding region of the YY1 gene, and to carry on research into the underlying mechanism of this disorder, parents and physicians are encouraged to visit the above-mentioned gene website and submit clinical information on newly diagnosed individuals.

Acknowledgments

We acknowledge all individuals and their parents who participated in the study described in Gabriele et al [2017], along with the agencies that funded that work.

Revision History

• 30 May 2019 (ma) Review posted live
• 23 April 2018 (gt, bdv) Original submission

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