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Background  Microtia is a congenital anomaly of ear that ranges in severity from mild structural abnormalities to complete absence of the outer ears. Concha-type microtia is considered to be a mild form. The H6 family homeobox 1 transcription factor gene ( HMX1 ) plays an important role in craniofacial structures development. Copy number variations (CNVs) of a downstream evolutionarily conserved enhancer region (ECR) of  Hmx1  associated with ear and eye abnormalities have been reported in different animals, but not yet in human. To date, no genetic defects responsible for isolated human microtia has been reported except for mutations in  HOXA2 . Here we recruited five Chinese families with isolated bilateral concha-type microtia, and attempt to identify the underlying genetic causes.    Methods  Single Nucleotide polymorphism (SNP) array was performed to map the disease locus and detect CNVs on a genome scale primarily in the largest family (F1). Whole genome sequencing was performed to screen all SNVs and CNVs in the candidate disease locus. Array comparative genomic hybridization (aCGH) was then performed to detect CNVs in the other four families, F2-F5. Quantitative real-time polymerase chain reaction (qPCR) was used to validate and determine the extent of identified CNVs containing  HMX1 -ECR region. Precise breakpoints in F1 and F2 were identified by gap-PCR and sanger sequencing. Dual-luciferase assays were used to detect the enhancer function. qPCR assays were also used to detect  HMX1 -ECR CNVs in 61 patients with other types mictrotia.    Results  Linkage and haplotype analysis in F1 mapped the disease locus to a 1.9 Mb interval on 4p16.1 containing  HMX1  and its downstream ECR region. Whole genome sequencing detected no potential pathogenic SNVs in coding regions of  HMX1  or other genes within the candidate disease locus, but it detected a 94.6 Kb duplication in an intergenic region between  HMX1  and  CPZ . aCGH and qPCRs also revealed co-segregated duplications in intergenic region downstream of  HMX1  in the other four families. The 21.8 Kb minimal overlapping region encompassing the core sequences consensus with mouse ECR of Hmx1. Luciferase assays confirmed the enhancer function in human sequences, and proved that HOXA2 could increase its enhancer activity. No CNVs were detected in  HMX1 -ECR regions in 61 patients with other type of microtia.    Conclusion  Duplications involving long range  HMX1  enhancers are associated with human isolated bilateral concha-type microtia. We add to evidences in human that copy number variations in  HMX1 -ECR associates with ear malformations, as in other species. This study also provides an additional example of functional conserved non-coding elements (CNEs) in humans.

Duplications involving the long range HMX1 enhancer are associated with human isolated bilateral concha-type microtia