Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families

Abstract

The 15q11.2 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 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 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 15q1l.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 (FAT3) 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¯ = 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.

AHDC1 missense mutations in Xia-Gibbs syndrome

“…Although FAT3 has not been definitively associated with a Mendelian disorder, recently a FAT3 variant has been implicated as a potential contributor to autism spectrum disorder (ASD). 29 Further, the AHDC1 de novo missense mutation in individual 1 was classified as LB according to ACMG criteria. This classification was supported by the observation of different alleles at the same amino acid position in two individuals in the gnomAD database—although those alleles were not observed in the gnomAD reported “normal” (control) cohort and may also have had disease association.…”

The Utilization of MS-MLPA as the First-Line Test for the Diagnosis of Prader–Willi Syndrome in Thai Patients

“…This microdeletion, involving TUBGCP5, CFYIP1, NIPA1, and NIPA2 genes, is known to cause neurological, cognitive, or behavioral problems in affected individuals as well as in individuals with PWS with deletion. [28][29][30] Distinguishing the molecular mechanism of the disease is helpful in better understanding the condition, and this information is for personalized management and counseling. The recurrence risk of PWS in the subsequent pregnancy is typically less than 1%.…”

From tip to toe – dressing centrioles in γTuRC

“…The identification of γTuRC populations with distinct, sub-centrosomal distribution and function warrants a more precise and differentiated terminology when referring to centrosomal γTuRC. Moreover, a more detailed analysis of γTuRC subpopulations is required in experiments where centrosomal γTuRC localization and activity are used as readouts, including the study of mutations in γTuRC subunits and regulators that have been linked to human disorders (Baldwin et al, 2021;Bond et al, 2005;Da Palma et al, 2020;Griffith et al, 2008;Gungor et al, 2021;Hassan et al, 2007;Hull et al, 2019;Issa et al, 2013;Martin et al, 2014;Maver et al, 2019;Mitani et al, 2019;Pagnamenta et al, 2012Pagnamenta et al, , 2016Puffenberger et al, 2012;Rafi and Butler, 2020;Scheidecker et al, 2015;Tan et al, 2014). In the absence of such analysis, the findings have to be interpreted with caution.…”