Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf–Hirschhorn syndrome

Abstract

BackgroundWolf–Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome involving variable size deletions of the 4p16.3 region. Seizures are frequently, but not always, associated with WHS. We hypothesised that the size and location of the deleted region may correlate with seizure presentation.MethodsUsing chromosomal microarray analysis, we finely mapped the breakpoints of copy number variants (CNVs) in 48 individuals with WHS. Seizure phenotype data were collected through parent-reported answers to a comprehensive questionnaire and supplemented with available medical records.ResultsWe observed a significant correlation between the presence of an interstitial 4p deletion and lack of a seizure phenotype (Fisher's exact test p=3.59e-6). In our cohort, there were five individuals with interstitial deletions with a distal breakpoint at least 751 kbp proximal to the 4p terminus. Four of these individuals have never had an observable seizure, and the fifth individual had a single febrile seizure at the age of 1.5 years. All other individuals in our cohort whose deletions encompass the terminal 751 kbp region report having seizures typical of WHS. Additional examples from the literature corroborate these observations and further refine the candidate seizure susceptibility region to a region 197 kbp in size, starting 368 kbp from the terminus of chromosome 4.ConclusionsWe identify a small terminal region of chromosome 4p that represents a seizure susceptibility region. Deletion of this region in the context of WHS is sufficient for seizure occurrence.

Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

“…CMA yields significant rates of pathogenic or potentially pathogenic (VOUS) results [2,11,12,13,14,15,16,17,18,19,20], which have clinical utility for the case-by-case clinical management of individuals with these individually rare disorders [23,24,25,26,27,28,29,30,31,32,33,34]. …”

“…Collectively this trend has resulted in corresponding increases in the clinical value of CMA testing [11,12,13,14,15,16,17,18,19,20,21,24,25,26,27,28,29,30,31,32,33,34]. In addition to guidelines on the clinical indications for CMA, the American College of Medical Genetics and Genomics (ACMG) has issued guidance on the appropriate content and design of such arrays and specifically opined that, “It is desirable to have enrichment of probes targeting dosage-sensitive genes known to result in phenotypes consistent with common indications for a genomic screen (e.g., intellectual disability, developmental delays, autism, and congenital anomalies)” [22].…”

Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

“…An unselected consecutive referral base, with a substantial nonspecialty physician referral component, lack of bias toward selected subgroups (e.g., exclusion of research enriched population of WHS/4p-cohort in the present series) [41], and the active offering of testing to the most recent clinical indication for CMA, ASD, which has an expectably lower rate of such findings [13–15], would be expected to result in a lower overall diagnostic yield in the present series. However, the overall detection rate for clinically established pathogenic CNVs of 9.2% is equivalent or higher than other reported series/platforms [7–17] despite the inherent bias toward lower rates based on the unselected referral base and focus on ASD.…”

Wolf-Hirschhorn Syndrome (WHS), A Case Report and Review of Literature Submit Manuscript

“…There are risks involved with an amniocentesis, such as fetal injury, for example, postural deformities if the amniocentesis is performed earlier than the suggested weeks, in addition to the risk of preterm labor, respiratory distress and chorioamnionitis. An amniocentesis demonstrated a female karyotype with a satellite chromosome 4 short arm and mosaicism for an additional marker chromosome (47, XX, 4ps, +mar (8)/46, XX, 4ps) [17]. Genetic counseling was provided to the couple with a description of the prenatal karyotype.…”