Detection of mutually exclusive mosaicism in a girl with genotype‐phenotype discrepancies

Abstract

Discordance between clinical phenotype and genotype has multiple causes, including mosaicism. Phenotypes can be modified due to tissue distribution, or the presence of multiple abnormal cell lines with different genomic contributions. We have studied a 20-month-old female whose main phenotypes were failure to thrive, developmental delay, and patchy skin pigmentation. Initial chromosome and SNP microarray analysis of her blood revealed a non-mosaic ~24 Mb duplication of 15q25.1q26.3 resulting from the unbalanced translocation of terminal 15q to the short arm of chromosome 15. The most common feature associated with distal trisomy 15q is prenatal and postnatal overgrowth, which was not consistent with this patient’s phenotype. The phenotypic discordance, in combination with the patchy skin pigmentation, suggested the presence of mosaicism. Further analysis of skin biopsies from both hyper- and hypopigmented regions confirmed the presence of an additional cell line with the short arm of chromosome X deleted and replaced by the entire long arm of chromosome 15. The Xp deletion, consistent with a variant Turner Syndrome diagnosis, better explained the patient’s phenotype. Parental studies revealed that the alterations in both cell lines were de novo and the duplicated distal 15q and the deleted Xp were from different parental origins, suggesting a mitotic event. The possible mechanism for the occurrence of two mutually exclusive structural rearrangements with both involving the long arm of chromosome 15 is discussed.

Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function

“…Interestingly, IUGR and failure to thrive have also been described in these patients ( 2 , 4 , 5 , 11 , 18 , 33 , 35 , 40 , 43 , 45 , 46 , 53 , 55 ). Thus, triplication of the IGF1R gene does not seem to be sufficient to cause somatic overgrowth.…”

“…To the best of our knowledge, up to now, 96 patients with chromosome 15q duplication have been reported in literature. Among these, 28 patients showed distal 15q tetrasomy due to a mosaicism or to a neocentromer marker chromosome (NMC) ( 2 , 3 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ) and the others had 15q distal trisomy ( 1 , 2 , 3 , 4 , 5 , 8 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ). The duplication of 15q chromosome can be classified in pure and impure forms, based on the presence of another chromosome abnormality (e.g.…”

“…Up to now, more than seventy patients with chromosome 15q terminal duplication have been reported ( 1 ). The majority of them have a terminal duplication with a proximal breakpoint ranging from 15q25.1 or 15q26.1 to the terminus ( 2 ). This structural chromosomal abnormality causes a common phenotype that includes prenatal and postnatal overgrowth, intellectual disability, characteristic craniofacial dimorphism and renal abnormalities ( 3 ), resulting in the so-called 15q overgrowth syndrome.…”

“…This structural chromosomal abnormality causes a common phenotype that includes prenatal and postnatal overgrowth, intellectual disability, characteristic craniofacial dimorphism and renal abnormalities ( 3 ), resulting in the so-called 15q overgrowth syndrome. However, failure to thrive and/or intrauterine growth retardation (IUGR) have been reported in some patients with chromosome 15q terminal duplication ( 2 , 4 , 5 ), thus suggesting that triplication of the IGF1R gene does not seem to be sufficient to cause somatic overgrowth.…”

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting

“…Prevalence data are not available for alopecia areata (23, 400, 403) and for cutis verticis gyrata (402,404,405,406) though case reports exist. Whorling skin pigmentation patterns, such as hypomelanosis of Ito, may accompany mosaic karyotypes (407). The prevalence of other skin conditions does not differ by karyotype (399).…”