PURA- Related Neurodevelopmental Disorders

Excerpt

Clinical characteristics: PURA-related neurodevelopmental disorders (PURA-NDDs) comprise PURA syndrome caused by a heterozygous PURA pathogenic variant and 5q31.3 deletion syndrome caused by a nonrecurrent 5q31.3 deletion encompassing all or part of PURA. PURA-NDDs are characterized by moderate-to-severe neurodevelopmental delay; most individuals are non-speaking and many lack independent ambulation. Early-onset issues can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements (dystonia, dyskinesia, and dysconjugate eye movements), and abnormal vision. Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur but are less common.

Diagnosis/testing: The diagnosis of PURA syndrome is established in a proband with a heterozygous PURA pathogenic variant (~93% of individuals with a PURA-NDD); the diagnosis of 5q31.3 deletion syndrome is established in a proband with a nonrecurrent 5q31.3 deletion encompassing all or part of PURA (~7% of individuals with a PURA-NDD) identified by molecular genetic testing.

Management: Treatment of manifestations: PURA-NDDs are incurable genetic disorders that are managed supportively and symptomatically. Ongoing routine care by a multidisciplinary team is recommended including treatment and/or therapy for developmental delays, neurologic findings (hypotonia, seizures, abnormal movements), speech and language disorders, feeding difficulties, apnea, visual impairment, and malformations of the heart, genitalia in males, kidneys and/or urinary tract, and skeleton (hip dysplasia and scoliosis).

Surveillance: Long-term follow up to assess neurologic findings (such as seizures or suspected seizures; new manifestations such as changes in tone and/or movement disorders); developmental progress and educational needs; speech and language progress and changes (including reassessment of alternative communication systems); vision; feeding issues including dysphagia; vitamin D deficiency and/or evidence of low bone density; and musculoskeletal complications (hip dysplasia and scoliosis).

Genetic counseling: PURA-NDDs – including PURA syndrome and 5q31.3 deletion syndrome – are autosomal dominant disorders.

Almost all individuals diagnosed with PURA syndrome have the disorder as the result of a de novo constitutional PURA pathogenic variant. Rarely, individuals have the disorder as the result of a postzygotic somatic mosaic pathogenic variant or a pathogenic variant inherited from a heterozygous or mosaic parent. The risk to the sibs of the proband depends on the genetic status of the parents: if a parent of the proband is affected and/or is known to have the PURA pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the PURA pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental gonadal mosaicism (the recurrence risk for PURA syndrome due to parental gonadal mosaicism is expected to be higher than the standard parental gonadal mosaicism risk of <1% because loss-of-function variants in PURA have a selective advantage resulting in clonal expansion).

To date, all reported 5q31.3 deletions have been de novo. If neither parent has a detected 5q31.3 deletion or a predisposing chromosomal rearrangement, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the possibility of parental gonadal mosaicism.

Once an intragenic pathogenic variant in PURA or a 5q31.3 chromosomal deletion encompassing all or part of PURA has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.