7p22.1 microduplication syndrome: Clinical and molecular characterization of an adult case and review of the literature

Abstract

A new 7p22.1 microduplication syndrome characterized by intellectual disability, speech delay and craniofacial dysmorphisms, such as macrocephaly, hypertelorism and ear anomalies, has been outlined by the description of two patients with interstitial microduplications confined to 7p22.1 and the recently defined minimal overlapping 430 kb critical region including five genes. Here we report on the first adult patient aged 35 years with moderate intellectual disability, psychomotor delay, facial dysmorphisms, cryptorchidism and cardiac anomalies, who carries two close microduplications at 7p22.1 of about 900 and 150 kb, respectively. The proximal smaller duplication includes three coding genes and maps outside the minimal described overlapping duplicated region, while the larger one represents the smallest 7p22.1 microduplication reported so far, as it encompasses the entire minimal region with only four additional genes. We compare the phenotype of our patient with that of the few reported cases and discuss on candidate genes in order to enhance the knowledge on genotype–phenotype correlation in 7p22.1 duplication syndrome.

Introduction

Duplications of the short arm of chromosome 7 are a relatively rare finding. Most of them are complex rearrangements resulting from a differently sized and positioned parental balanced translocation or inversion (for review see Papadopoulou et al., 2006). Only a few patients with pure 7p duplications have been reported, including sixteen cases detected by standard cytogenetic analysis (Papadopoulou et al., 2006). The common clinical signs include intellectual disability (ID), hypotonia, craniofacial dysmorphism (large anterior fontanel, high and/or broad forehead, ocular hypertelorism, downslanting palpebral fissures, low set and/or malformed ears, abnormal palate, micrognathia and/or retrognathia), abnormal palmar creases, skeletal and cardiovascular abnormalities. Later on only five 7p microduplications detected by array-CGH have been characterized. All of them, except for the approximately 5 Mb microduplication involving the terminal region (Zahed et al., 2007), are interstitial microduplications located in the 7p22 band (AlFardan et al., 2011, Chui et al., 2011, Pebrel-Richard et al., 2014, Preiksaitiene et al., 2012). Interestingly, the 2.4 Mb duplication spanning 7p22.1p22.2 reported in an 11 year-old female with a “classic 7p duplication phenotype” was inherited from the mother who presented only with some facial features in common with her daughter and mild cognitive disability (AlFardan et al., 2011). The de novo 1.7 Mb 7p22.1 duplication detected by Chui et al. in a 28 month-old male patient was associated with a clinical phenotype characterized by speech delay, the typical dysmorphic features of 7p duplication, and skeletal anomalies (Chui et al., 2011). The 1 Mb duplication involving 7p22.1 described by Preiksaitiene et al. is the smallest reported up to date (Preiksaitiene et al., 2012). The carrier was a 14 year-old patient with mild ID, psychomotor delay, moderate hydrocephalus, several craniofacial dysmorphic features, skeletal anomalies and truncal obesity. Given that 7p22.1 microduplications are associated with common clinical features recorded in patients with larger duplications as well, the region indicated by Preiksaitiene et al. (2012) has been proposed as critical for a 7p22.1 recognizable microduplication syndrome which hallmarks are developmental delay, distinctive facial features and skeletal anomalies. More recently, Pebrel-Richard et al. has described a 3 year-old boy carrying a 7p22.2p22.1 microduplication of about 1.6 Mb who displayed psychomotor and speech delay, several craniofacial dysmorphisms typical of 7p duplication plus joint hypermobility, truncal stereotypies and attention deficit disorder (ADD) (Pebrel-Richard et al., 2014). This microduplication partially overlaps with the smallest duplicated region reported by Preiksaitiene et al. (2012), allowing to highlight a minimal critical region of 430 kb encompassing five genes: TNRC18, FBXL18, ACTB, FSCN1 and RNF216.

We report on the aCGH characterization of an adult patient carrying the smallest 7p22.1 microduplication detected so far, and compare his phenotype to that of the previously described patients subject to cytogenomic investigation.