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A rare genetic neurodevelopmental syndrome characterized by mild intellectual disability, developmental delay, dysmorphic facial features, growth- and feeding problems, hypotonia, epilepsy, behavioral problems and a variety of congenital abnormalities.
ORPHA:500163Classification level: Disorder
- SIN3A-related intellectual disability syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant
- Age of onset: Antenatal, Neonatal
- ICD-10: Q87.8
- OMIM: -
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
Approximately 40 individuals with mutations in SIN3A have been reported. Males and females are equally affected.
Individuals may present with growth or feeding difficulties, developmental delay and/or intellectual disability. Overall intellectual disability is mild (no cognitive impairment in 25%). Intelligence testing typically shows a disharmonic profile favoring verbal IQ. Facial features include a tall, broad forehead, down-slanting palpebral fissures, triangular face with a pointed chin and a thin upper lip. Half of the patients show epilepsy and/or hypotonia. A third have a psychiatric or behavioral condition, including attention deficit and hyperactivity disorder, autism spectrum disorder, aggressive behavior, obsessive compulsory disorder, depression, psychosis, anxiety and schizoaffective disorder. Other reported manifestations are microcephaly, short stature, palatal defect, hearing loss, ocular abnormalities, and hyperlaxity. Brain abnormalities including ventriculomegaly, anomalies of the corpus callosum, cerebellar atrophy, or Chiari 1 malformation are present in a minority. In a minority of patients, congenital anomalies such as pelvic kidney, atrial/ventricular septal defects (ASD/VSD), cystocele, urethrocele, and thickened aortic valve may occur. Individuals with 15q24 microdeletion syndrome have a more heterogeneous phenotype with moderate to severe intellectual disability and additional features depending on the other genes involved in the deletion.
The disorder is either caused by mutations in Switch-insensitive 3 transcription regulator family member A (SIN3A; 15q24.2) or microdeletions, of various sizes, in the chromosome region 15q24 (15q24 microdeletion syndrome). The microdeletions often, but not always, encompass SIN3A.
Most cases will be identified by unbiased genetic testing including chromosomal microarray, intellectual disability gene panels, whole exome or whole genome sequencing. Targeted genetic testing is possible.
Most cases are identified using an unbiased diagnostic approach for syndromic forms of neurodevelopmental delay or intellectual disability.
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Transmission is autosomal dominant. Genetic counseling should be offered to parents of affected individuals. The majority of cases are sporadic and thus in these cases the sibling recurrence risk is low. If one of the parents is affected, recurrence risk is 50%.
Management and treatment
A multidisciplinary team approach should be considered including a pediatrician, clinical geneticist, and psychiatrist. Referral to other specialists (e.g. neurologist, ophthalmologist) is indicated when specific problems are suspected. Development should be closely monitored and physical and speech therapy should be considered. Early intervention for psychiatric or behavioral conditions is important to ensure optimal treatment and outcome. Clinicians should be aware that affected individuals will likely have a disharmonic intelligence profile; this easily leads to overestimating of the self-management capabilities of patients. Screening of congenital defects (pelvic kidney, ASD/VSD, cystocele, urethrocele, thickened aortic valve) is recommended after diagnosis. Imaging (e.g MRI) should not be performed routinely, but considered on clinical indication, for instance in the occurrence of seizures.
There is insufficient longitudinal follow-up data to determine life expectancy, although survival into adulthood is typical. Individuals will likely require some degree of support throughout life. Quality of life is greatly influenced by the occurrence of psychiatric and/or neurological conditions.
A summary on this disease is available in Español (2020) Français (2020) Nederlands (2020)