A Novel 4q32.3 Deletion in a Child: Additional Signs and the Role of MARCH1

Abstract

The 4q deletion syndrome is an uncommon condition manifesting with broad clinical expression and phenotypic variability. We report a 5-year-old boy affected by 4q deletion syndrome who showed minor craniofacial features, growth failure, mild developmental delay, severe speech delay, and marked irascibility and aggressivity. Moreover, he showed precocious and crowded primary dentition, digital hyperlaxity, and congenital bilateral adducted thumbs, signs which were previously unreported in the syndrome. The array comparative genomic hybridization analysis revealed a 4q partial terminal deletion of ∼329.6 kb extending from 164.703.186 to 165.032.803 nt, which includes part of MARCH1 (membrane associated ring-CH-type finger 1) gene (OMIM#613331). Same rearrangement was found in his healthy mother. Clinical phenotype of the child and its relationship to the deleted region is presented with a revision of the cases having the same copy number losses from the literature and genomic variant databases.

Keywords: 4q deletion syndrome; MARCH1 gene; adducted thumbs; aggressive behavior; craniofacial features; marked speech delay; precocious dentition.

Fig. 1

The patient at the age of 24 months showing some minor craniofacial features, including rounded and very high forehead, long eyebrows, epicanthal folds, low-set ears, long philtrum, thin lips, large nasal bridge with round tip, micro- and retrognathia.

Fig. 2

Genomic localization of proband's deletion in 4q32.3 region (164.703.186–165.032.803)x1 and view of regulatory and transcriptional features of MARCH1 gene. ( A ) Snapshot of UCSC Genome Browser view showing the main gene structural and regulatory features. Three promoter sequences (from right to left: MARCH1_1, MARCH1_2, and MARCH1_3) annotated from EPDnew v.06 of MARCH1 are embedded in the blue box. The consensus coding sequence (CCDS) set is composed of CCDS54814 and CCDS3806 (green) assigned for protein coding transcripts. The size of copy number variant (CNV) deletion detected in this study is highlighted in light blue. ( B ) Snapshot of ensemble browser view listing all 15 transcripts of the gene.

Fig. 3

Overview of tissues expression of MARCHF1 gene. The modified image is availabe from Human Protein Atlas v20.1 (www.proteinatlas.org/). The overview of MARCHF1 expression pattern taken from NX consensus dataset (https://www.proteinatlas.org/ENSG00000145416-MARCH1/tissue) identifies RNA tissue specificity in the brain (yellow bar) and in the lymphoid tissues (gray bar). NX is the consensus transcript expression levels summarized per gene in 62 tissues based on transcriptomics data from three sources: HPA, GTEx and FANTOM5. The consensus normalized expression (“NX”) value is calculated as the maximum NX value for each gene in the three data sources.