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15q13.3 microdeletion syndrome
15q13.3 microdeletion (microdel15q13.3) syndrome is characterized by a wide spectrum of neurodevelopmental disorders with no or subtle dysmorphic features.
ORPHA:199318Classification level: Disorder
Its prevalence is unknown; nearly 150 cases have been reported, including a subset of healthy relatives of affected individuals. Males are more likely to be symptomatic.
The syndrome manifests in childhood or later in life. Patients present with developmental delay, mainly in speech acquisition, cognitive impairment in about half of the cases (usually mild, sometimes moderate to severe), idiopathic generalized epilepsy (IGE, including childhood or juvenile absence epilepsy, juvenile myoclonic epilepsy (see these terms) and epilepsies with generalized tonic-clonic seizures), neurobehavioral disorders of the autistic or psychotic spectrum (including impaired expressive language, poor eye contact, repetitive movements, hyperactivity, impulsive and/or aggressive behavior, and disturbed social interactions). Subtle dysmorphic features may be present (down-slanting palpebral fissures, prominent nasal tip, large ears, strabismus, clinodactyly of the 5th finger, pigmented naevi). Short stature, macrocephaly and hypotonia are common. Congenital heart defects are rare. Asymptomatic carriers may have a history of learning difficulties.
The syndrome is due to submicroscopic deletions in the proximal 15q region, known for its instability and high density of low-copy repeat (LCR) sequences mediating non-allelic homologous recombination (NAHR), resulting in genomic rearrangements. Six breakpoints (BPs), clustered in LCRs, are mapped to the 15q11q14 region. 15q13.3 recurrent 1.5 Mb deletion between BP4 and BP5, results in loss of six known genes including CHRNA7. Haplo-insufficiency of CHRNA7 might be responsible for most of the neurodevelopmental disorders associated with the deletion. Occasional larger BP3-BP5 deletions do not seem to differ clinically.
Diagnosis should be suspected in any infant or child with developmental delay/intellectual disability, autism, schizophrenia, seizures, hypotonia, and/or minor dysmorphic features. Microdel15q13.3 is not detected using conventional karyotyping (G-banding) but can be detected by fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization (aCGH).
Differential diagnosis comprises the other causes of intellectual deficit, schizophrenia, autism and epilepsy. Genetic testing rules out the other 15q proximal anomalies associated with a similar clinical picture.
Prenatal diagnosis is possible through chorionic villus sampling or amniocentesis analyzed by cytogenetic (FISH) and molecular methods.
Around 25% of deletions occur de novo while 75% are inherited in an autosomal dominant manner with variable expressivity and incomplete penetrance. Of the inherited cases, approximately 25% are inherited paternally and 75% maternally. Genetic counseling should be offered cautiously as the syndrome may be either sporadic or familial. In cases where the deletion is inherited, siblings have a 50% risk of inheriting the deletion. However, not all carriers will develop the syndrome.
Management and treatment
The clinical picture should guide treatment. Early educational interventions are recommended in patients with cognitive impairment and autism. Epilepsy, autism and/or schizophrenia should be treated according to standard guidelines. Cardiac ultrasound should be performed in all carriers to exclude a congenital heart defect. Management in healthy carriers is not necessary, although medical awareness of signs that may become apparent later in life, e.g. schizophrenia, is recommended.
Prognosis depends on the clinical features. Carriers with learning difficulties in childhood often function normally in adulthood. Survival does not seem to be reduced in the absence of a congenital heart defect.