Glomerulopathy in patients with distal duplication of chromosome 6p

Trisomy of the distal fragment of chromosome 6p is extremely rare. So far, less than 50 patients have been reported worldwide, each presenting with a distinct region of aberration, unique chromosomal breakpoints and considerable phenotypic variability [1‐3]. Nevertheless, a few features appear consistent: pre- and post-natal growth retardation, developmental delay, intellectual disability, dysmorphia, and congenital malformations, most commonly heart, renal and ocular defects (Table 1).

The Central European descent girl with a complex genomic disorder involving chromosome 6p presented with persistent proteinuria from the age of 9 months. Family history was unremarkable. Birth weight, length and head circumference were below the 3^rd centile. General hypotonia and failure to thrive prompted a detailed evaluation, which revealed dysmorphia and multiple congenital defects, including corpus callosum hypoplasia, moderate internal hydrocephalus, brain asymmetry, subvalvular pulmonary stenosis and partial synostosis of 1^st and 2^nd ribs. Distinctive facial features: craniosynostosis, facial asymmetry, high broad front with frontal bossing, microphthalmia with ptosis and blepharophimosis, broad prominent nose bridge with relatively small nose, microstomia, narrow lips and low-set dysplastic ears were observed. Nystagmus, strabismus and severe bilateral hearing impairment developed and developmental milestones were delayed; she was able to sit without support at 14 months and started walking at 39 months of age. At 13 years she still cannot speak and communicates by basic gestures. She understands and follows simple orders.

In most cases reported, distal trisomy 6p results from an unbalanced inheritance of a parental translocation. The clinical picture of these patients is influenced by the accompanying monosomy of an another chromosomal region. Here, we present an extremely rare case of a pure chromosome 6p duplication resulting from de novo reverse duplication (Fig. 1d). A review of the published cases along with database search [1‐7] allowed for identification of 12 individuals whose region of duplication was partially overlapping with the region affected in our case (Fig. 1c).

Renal abnormalities have been observed in approximately half of the patients. Congenital abnormalities of the kidney and urinary tract (CAKUT), such as hypoplastic kidneys, renal cysts, vesicoureteral reflux and hydronephrosis have been described [4, 6, 7]. In addition, proteinuria has been reported in eight patients. These included two cases of a pure 6p duplication [5, 7] and six with a duplication resulting from an unbalanced parental translocation (after [4, 7‐9]). The presented case is, however, the first to be comprehensively studied for mutations in all known glomerulopathy-associated genes to rule out co-incidence of two genetic entities.

Based on the findings reported to date, we estimate that at least 15–20 % of patients with terminal 6p duplication might develop proteinuria. This may be an underestimate since kidney disease may still be clinically silent at the time when the genetic diagnosis is established. The age at onset of proteinuria was less than three years in 7/9 subjects including the present case; the remaining two developed glomerular failure before the age of ten years. Six patients underwent kidney biopsy. Of these, three were diagnosed with FSGS, while membranous glomerulonephritis, focal mesangial hypercellularity and periglomerular fibrosis was reported each in one case. Five patients underwent kidney transplant at age 4–18 years; so far no disease recurrence has been reported, suggesting an intrinsic renal rather than a systemic abnormality as the cause of glomerulopathy. Resistance to steroids was observed In two treated subjects including the present case.

Giardino et al. [5] proposed 6p22– > 6pter as the most likely localization of the putative locus of the causative gene(s). Taking into account breakpoints of a few patients published afterwards including our case, we are able to further narrow the smallest region of the overlap to the 6p25 band. The assigned region comprises 29 protein-coding genes and three miRNAs (Additional file 1: Table S1). None of the established glomerulopathy-associated genes is located within the region of interest. A recent review described candidate genes expected to be involved in phenotypic features of the distal chromosome 6p duplication syndrome [6]. Of these, only one, namely FOXC1, was identified as a player in kidney development and functioning. FOXC1 encodes a transcription factor that, along with Lmx1b, interacts synergistically through a common enhancer site to regulate the expression of podocyte specific genes, including NPHS2 [10]. Mutations in FOXC1 have previously been described in patients with Axenfeld-Rieger anomaly and/or glaucoma (OMIM*601090). Haploinsufficiency studies have identified FOXC1 as a strongly dosage sensitive gene, supporting the hypothesis that FOXC1 may be pathogenic if overexpressed.

Our findings reinforce the hypothesis that the proximal 6p region contains gene(s) involved not only in kidney development but also in postnatal podocyte function. We recommend monitoring of kidney morphology and function in all patients with constitutive distal 6p duplication. Conversely, in patients with features of CAKUT and/or SRNS/FSGS who have associated syndromic disease array-CGH evaluation for chromosome 6p duplication should be performed.