De Novo Mosaic 6p23-p25.3 Tetrasomy Caused by a Small Supernumerary Marker Chromosome Presenting Trisomy Distal 6p Phenotype: A Case Report and Literature Review

Abstract

Small supernumerary marker chromosomes (sSMCs) derived from the chromosome 6 short arm are rare and their clinical significance remains unknown. No case with sSMC(6) without centromeric DNA has been reported. Partial trisomy and tetrasomy of distal 6p is a rare but clinically distinct syndrome. We report on a de novo mosaic sSMC causing partial tetrasomy for 6p23-p25.3 in a male infant with symptoms of being small for gestational age, microcephaly, facial dysmorphism, congenital eye defects, and multi-system malformation. Conventional cytogenetic analysis revealed a karyotype of 47,XY,+mar [25]/46,XY [22]. Array comparative genomic hybridization (aCGH) revealed mosaic tetrasomy of distal 6p. This is the first case of mosaic tetrasomy 6p23-p25.3 caused by an inverted duplicated neocentric sSMC with characteristic features of trisomy distal 6p. Comparison of phenotypes in cases with trisomy and tetrasomy of 6p23-p25.3 could facilitate a genotype–phenotype correlation and identification of candidate genes contributing to their presentation. The presentation of anterior segment dysgenesis and anomaly of the renal system suggest triplosensitivity of the FOXC1 gene. In patients with microcephaly growth retardation, and malformation of the cardiac and renal systems, presentation of anterior segment dysgenesis might be indicative of chromosome 6p duplication, and aCGH evaluation should be performed for associated syndromic disease.

Cytogenomic characterization of small supernumerary marker chromosomes in patients with pigmentary mosaicism

“…The first reported patient showed tetrasomy 6p not associated with sSMCs (Ryan et al, 2007), and the second reported case was very similar to our patient, who showed an inverted duplicated sSMC from 6p (Syu et al, 2022). Mosaic tetrasomy of the distal 6p caused by sSMC was associated with multisystem malformations, including craniofacial, cardiovascular, genitourinary, ophthalmological, and hearing problems, which was attributed to a duplication of 14.337 Mb in the 6p23-p25.3 region, which involved 65 genes (Syu et al, 2022). Our patient shares many of these clinical manifestations, including craniofacial, cardiovascular, genitourinary, and hearing defects.…”

“…In addition, PM has not previously been reported in patients with trisomy or tetrasomy 6p. Our patient showed a larger duplicated region than the case reported by Syu et al, 2022 ; the 6p25.3p22.1 region duplicated in our patient involved 274 genes. Among the affected genes, FOXC1 and BMP6 were detected, which have been suggested to contribute to the 6p tetrasomy phenotype.…”

“…Although FOXC1 has also been associated with kidney development, renal defects were not observed in this patient. BMP6 is located at 6p24.3, and its overexpression is associated with craniofacial abnormalities ( Liehr, 2021 ; Villa, 2007 ; Syu et al, 2022 ).…”