Abstract
Chromosome 15q11-q13.1 duplication is a common copy number variant associated with autism spectrum disorder (ASD). Most cases are de novo, maternal in origin and fully penetrant for ASD. Here, we describe a unique family with an interstitial 15q11.2-q13.1 maternal duplication and the presence of somatic mosaicism in the mother. She is typically functioning, but formal autism testing showed mild ASD. She had several congenital anomalies, and she is the first 15q Duplication case reported in the literature to develop unilateral renal carcinoma. Her two affected children share some of these clinical characteristics, and have severe ASD. Several tissues in the mother, including blood, skin, a kidney tumor, and normal kidney margin tissues were studied for the presence of the 15q11-q13.1 duplication. We show the mother has somatic mosaicism for the duplication in several tissues to varying degrees. A growth competition assay in two types of stem cells from duplication 15q individuals was also performed. Our results suggest that the presence of this interstitial duplication 15q chromosome may confer a previously unknown growth advantage in this particular individual, but not in the general interstitial duplication 15q population.
Highlights
A 35-year-old female underwent clinical and neuropsychiatric evaluation after her two affected sons, who have maternal interstitial 15q11.2-q13.1 duplication (Figure 1: IV-1 and IV2) were seen at Le Bonheur Children’s Hospital
Inherited int dup15 is rare, with only one published case involving the inheritance of a maternal duplication from the mother (Boyar et al, 2001), some families with paternal duplication inherited from the father have been documented (Browne et al, 1997; Cook et al, 1997; Boyar et al, 2001; Veltman et al, 2005; Urraca et al, 2013; Al Ageeli et al, 2014)
The mother is only mildly affected cognitively, but still on the autism spectrum by clinical observation and formal ADOS/ADI-R testing. The fact that her Fluorescence in situ hybridization (FISH) showed a significant decrease in the number of duplicated cells in both blood and skin raises the possibility that she may be mosaic for the duplication in the central nervous system (CNS) as well, decreasing the severity of her autism symptoms
Summary
A 35-year-old female underwent clinical and neuropsychiatric evaluation after her two affected sons, who have maternal interstitial 15q11.2-q13.1 duplication (int dup15) (Figure 1: IV-1 and IV2) were seen at Le Bonheur Children’s Hospital. A mild autism spectrum disorder (ASD) diagnosis was established at 34 year of age by the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) and Autism Diagnostic Interview, Revised (ADI-R) (Lord et al, 1989, 1994) She demonstrated an overall below average IQ of 75 on the Wechsler Abbreviated Scale of Intelligence second edition but there was significant discrepancy between reasoning domains with a low average Verbal Comprehension Index of 89 and well below average Perceptual Reasoning Index of 66. We identified in each culture that 1–35% of the cells had undergone additional chromosomal rearrangements, resulting in triplication events (Figure 3) These results indicate that int dup cells typically grow slower than control cells in mixed culture from unrelated individuals and that the duplication is unstable in cultured DPSC. At 5 years of age, he was administered the ADOS-2, Module 1 He had a Comparison Score of 10/10, suggesting a FIGURE 3 | Representative Fluorescence in situ hybridization (FISH) images from mixed culture analysis. She was negative for any known copy number variants and appears neurotypical
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