SETD2 Neurodevelopmental Disorders

Clinical description: SETD2 neurodevelopmental disorders (SETD2-NDDs) represent a clinical spectrum that most commonly includes various degrees of intellectual disability and behavioral findings (most typically an autism spectrum disorder), macrocephaly with or without ventriculomegaly, brain malformations (including Chiari 1 malformation and syringomyelia), and obesity with generalized overgrowth and advanced bone age. A specific, somewhat different phenotype (denoted SETD2-NDD with multiple congenital anomalies [MCA]) has been reported in association with a particular pathogenic variant, c.5218C>T (p.Arg1740Trp), which leads to a higher frequency of multiple congenital anomalies compared to those without this genetic change. Individuals with SETD2-NDD with MCA may have microcephaly, congenital heart malformations, urogenital anomalies, eye findings (specifically Coats disease of the retina), severe failure to thrive, hypotonia, hyponatremia, respiratory issues (tracheomalacia, frequent aspiration, hypoventilation), epilepsy, profound intellectual disability with limited-to-no speech, and distinctive craniofacial features.

Diagnosis/testing: The diagnosis of a SETD2-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in SETD2 identified by molecular genetic testing.

Management: Treatment of manifestations:

1. SETD2-NDD with or without macrocephaly/overgrowth. Nutritional management of obesity to include diet/exercise; consideration of growth hormone therapy in those with poor growth; standard treatment for developmental delay / autistic features, seizures, hypothyroidism, precocious puberty, hypotonia/hypermobility, scoliosis, refractive error / strabismus, hearing loss, congenital heart defects, and cryptorchidism.

2. SETD2-NDD with MCA. Feeding therapy to include consideration of a gastrostomy tube; supplemental oxygen therapy with consideration of tracheostomy in those with tracheomalacia/hypoventilation; sodium supplementation for those with hyponatremia; standard treatment for developmental delay, seizures, joint contractures, sensorineural/conductive hearing loss, Coats disease of the retina, congenital heart defects, cryptorchidism, dysplastic kidneys, and skeletal anomalies.

Surveillance:

1. SETD2-NDD with or without macrocephaly/overgrowth. Monitor for psychiatric symptoms, seizures, changes in tone, movement disorders, and developmental progress at each clinic visit; weight checks at home for obesity prevention starting in the second year of life; annual thyroid-stimulating hormone and free T4; clinical evaluation for precocious puberty and scoliosis at each visit during childhood; annual (or as clinically indicated) ophthalmology and audiology evaluations.

2. SETD2-NDD with MCA. Monitor for appropriate growth, evidence of aspiration, respiratory sufficiency, seizures, changes in tone, movement disorders, and developmental progress at each clinic visit; electrolyte panel to include sodium level to assess for hyponatremia at each visit during infancy; annual (or as clinically indicated) ophthalmology and audiology evaluations.

Genetic counseling: SETD2-NDDs are inherited in an autosomal dominant manner, although most affected individuals represent simplex cases (i.e., a single occurrence in a family). To date, transmission of a SETD2 pathogenic variant from a parent to a child has been reported in one family. If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Each child of an individual with a SETD2-NDD has a 50% chance of inheriting the SETD2 pathogenic variant. Once the SETD2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.