Genome-wide expression analysis in fibroblast cell lines from probands with Pallister Killian syndrome.

Maninder Kaur,Alisha B Wilkens,Ian D Krantz,Kosuke Izumi,Zhe Zhang,Nancy B Spinner,Kathryn C Chatfield,Laura K Conlin,Ken Mills

doi:10.1371/journal.pone.0108853

Abstract

Pallister Killian syndrome (OMIM: # 601803) is a rare multisystem disorder typically caused by tissue limited mosaic tetrasomy of chromosome 12p (isochromosome 12p). The clinical manifestations of Pallister Killian syndrome are variable with the most common findings including craniofacial dysmorphia, hypotonia, cognitive impairment, hearing loss, skin pigmentary differences and epilepsy. Isochromosome 12p is identified primarily in skin fibroblast cultures and in chorionic villus and amniotic fluid cell samples and may be identified in blood lymphocytes during the neonatal and early childhood period. We performed genomic expression profiling correlated with interphase fluorescent in situ hybridization and single nucleotide polymorphism array quantification of degree of mosaicism in fibroblasts from 17 Caucasian probands with Pallister Killian syndrome and 9 healthy age, gender and ethnicity matched controls. We identified a characteristic profile of 354 (180 up- and 174 down-regulated) differentially expressed genes in Pallister Killian syndrome probands and supportive evidence for a Pallister Killian syndrome critical region on 12p13.31. The differentially expressed genes were enriched for developmentally important genes such as homeobox genes. Among the differentially expressed genes, we identified several genes whose misexpression may be associated with the clinical phenotype of Pallister Killian syndrome such as downregulation of ZFPM2, GATA6 and SOX9, and overexpression of IGFBP2.

Highlights

Described by Pallister et al [1], [2] and later by Killian and Teschler-Nicola, Pallister Killian Syndrome (PKS) (OMIM #601803) known as tetrasomy 12p and isochromosome 12p mosaicism is a rare chromosomal aneuploidy with an estimated prevalence of 1/20,000 [3], [4]
In this study, using the skin fibroblast cell lines derived from 17 probands with PKS, we demonstrate that PKS probands have a unique gene expression signature, which is characterized by misexpression of many developmentally critical genes including multiple homeobox genes
Since many genetic developmental disorders are caused by the perturbation of proper regulation of gene expression during embryogenesis, our observation of a highly conserved pattern of abnormal gene expression of many developmentally critical genes fits very well with the pleiotropic phenotype seen in PKS

Summary

Introduction

Described by Pallister et al [1], [2] and later by Killian and Teschler-Nicola, Pallister Killian Syndrome (PKS) (OMIM #601803) known as tetrasomy 12p and isochromosome 12p mosaicism is a rare chromosomal aneuploidy with an estimated prevalence of 1/20,000 [3], [4]. PKS is characterized by tissue-specific mosaicism of a supernumerary isochromosome which is typically a metacentric chromosome composed of material from the short arm of chromosome 12: i(12)(p10) [5]. Individuals with PKS have four copies of the complete short arm of chromosome 12, rarely, probands may have a complete or partial duplication of 12p and still manifest the full PKS phenotype [6]. Typical features include cognitive impairment, prenatal overgrowth followed by postnatal growth deceleration, hypotonia, seizures, cutaneous hypo and/or hyperpigmentation, facial dysmorphia including a high forehead, broad nasal bridge, telecanthus, sparse fronto-temporal hair at birth, high arched or cleft palate, posterior helical ear pits, short neck, supernumerary nipples, limb and genitourinary anomalies, congenital heart defects and diaphragmatic hernias [9]

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