Clinical and Genetic Heterogeneity of the 15q13.3 Microdeletion Syndrome

Abstract

The 15q13.3 microdeletion is a recurrent CNV, presumably mediated by NAHR between segmental duplications in chromosome 15. The 15q13.3 deletion and duplication are associated with a wide range of clinical manifestations, such as intellectual deficits, seizures, autism, language and developmental delay, neuropsychiatric impairments, and behavioral problems illustrating incomplete penetrance and expressivity. This study comprises an evaluation of 106 symptomatic patients carrying the heterozygous deletion, as well as of 21 patients carrying the duplication, who have been described in previous studies. The analysis shows considerable heterogeneity for the manifestation of different key symptoms and familiar occurrence. Furthermore, 8 new patients are introduced. Convoluted familiar connections give new insights into the complexity of symptomatic manifestation. In previous studies, different opinions have been expressed as to the nature and precise location of the deletion breakpoints. Here, we show that not CHRNA7 and CHRFAM7A, but rather FAM7A or GOLGA8, serve as breakpoint regions concerning our patients. The deletion is described as heterogeneous in size. However, we assume that not only different breakpoints but also the imprecision of aCGH analysis on chromosome 15 due to segmental duplications accounts for the variability in size.

Human core duplicon gene families: game changers or game players?

“…Loss of individual GOLGA genes in mice or humans is not cell lethal, possibly due to functional redundancy between different copies. Palindromic GOLGA8 core duplicons promote recurrent chromosome 15q13.3 microdeletions that are associated with intellectual disability, schizophrenia, autism and epilepsy [48, 49] but there are currently no data that would suggest a causative role of GOLGA8 losses for the disease effects.…”

Chromosome 15q BP4-BP5 Deletion in a Girl with Nocturnal Frontal Lobe Epilepsy, Migraine, Circumscribed Hypertrichosis, and Language Impairment

“…Dibbens et al 11 described seven cases: three with juvenile myoclonic epilepsy; three with childhood absence epilepsy, and one with juvenile absence epilepsy. A single case of epilepsy was reported by Ben-Shachar et al; 14 two cases by van Bon et al, 6 and another one by Hassfurther et al 28 In a group of 18 individuals with microdel 15q13.3, Ziats et al 27 reported three cases with epileptic seizures: one with absence, one with GTCS, and one with NFLE. In most of these cases, epileptic treatment was followed with the standard practice according to the age of the affected individuals, the type of epilepsy and its related oucome.…”

“…Data collected by the literature are summarized in Table 1. 1,2,4,6,[9][10][11]14,24,[26][27][28] Case-reports with less than two subjects examined are not included. Among 117 individuals, the most frequent clinical manifestations were represented by DD/ID (76.9%), behavioral abnormalities (51.2%), speech impairment (42.7%), and epilepsy (30.7%).…”

Translational Study of Copy Number Variations in Schizophrenia

“…Notably, deletions and duplications at 7q11.23 are associated with autism spectrum disorder [ 41 , 42 , 43 , 44 ]. CNVs at 15q13.3 are associated with developmental disorders, intellectual disability, attention-deficit hyperactivity disorder, autism spectrum disorder, childhood-onset schizophrenia, and depression in addition to schizophrenia [ 32 , 36 , 45 , 46 ]. CNVs at proximal 16p11.2 are also associated with neurodevelopmental disorder, intellectual disability, attention-deficit hyperactivity disorder, depression, and autism [ 34 , 36 , 47 , 48 , 49 , 50 , 51 ].…”