Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms22041660
Keywords
15811.2 BP1-BP2 deletion; Burnside-Butler syndrome; clinical findings; cognition; neuropsychiatric behavior development; genomic characterization; exome sequencing; protein-protein interaction
Funding
- National Institute of Child Health and Human Development (NICHD) [HD02528]
- Kansas Intellectual and Developmental Disabilities Research Center (KIDDRC) [U54HD090216]
- National Center for Advancing Translational Sciences (NCATS) Clinical and Translational Science Award (CTSA) [TL1TR002368]
- National Institute of Mental Health [R01MH112734]
- National Library of Medicine [K01LM012870]
- KUMC Research Institute Clinical Pilot Research Grant Program
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The 15811.2 BP1-BP2 deletion syndrome is becoming increasingly common in patients with neurodevelopmental or ASD, with additional genomic variation likely influencing symptom expression. Whole-exome sequencing in affected families identified 453 genes with potentially damaging variants, shedding light on the genetic factors impacting symptoms in Burnside-Butler syndrome.
The 15811.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15811.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15811.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15811.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FATS) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes ((x) over bar = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.
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