Individual Clinically Diagnosed with CHARGE Syndrome but with a Mutation in KMT2D, a Gene Associated with Kabuki Syndrome: A Case Report.

Sonoko Sakata,Chihiro Tani,Akari Utsunomiya-Nakamura,Masao Kobayashi,Haruo Mizuno,Reiko Kagawa,Kohei Aoyama,Satoshi Okada,Shinichiro Miyagawa,Keiichi Hara,Tsutomu Ogata

doi:10.3389/fgene.2017.00210

Abstract

We report a Japanese female patient presenting with classic features of CHARGE syndrome, including choanal atresia, growth and development retardation, ear malformations, genital anomalies, multiple endocrine deficiency, and unilateral facial nerve palsy. She was clinically diagnosed with typical CHARGE syndrome, but genetic analysis using the TruSight One Sequence Panel revealed a germline heterozygous mutation in KMT2D with no pathogenic CHD7 alterations associated with CHARGE syndrome. Kabuki syndrome is a rare multisystem disorder characterized by five cardinal manifestations including typical facial features, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate intellectual disability, and postnatal growth deficiency. Germline mutations in KMT2D underlie the molecular pathogenesis of 52–76% of patients with Kabuki syndrome. This is an instructive case that clearly represents a phenotypic overlap between Kabuki syndrome and CHARGE syndrome. It suggests the importance of considering the possibility of a diagnosis of Kabuki syndrome even if patients present with typical symptoms and meet diagnostic criteria of CHARGE syndrome. The case also emphasizes the impact of non-biased exhaustive genetic analysis by next-generation sequencing in the genetic diagnosis of rare congenital disorders with atypical manifestations.

Highlights

CHARGE syndrome (OMIM #214800) is an autosomal dominant genetic disorder that was first reported in Pagon et al (1981)
We report a patient clinically diagnosed with typical CHARGE syndrome that fulfilled both Blake and Verloes criteria (Blake et al, 1998; Verloes, 2005), but who was genetically diagnosed with atypical KS based on the presence of a de novo KMT2D mutation and the absence of pathogenic variation in CHD7
The current patient met the diagnostic criteria of typical CHARGE syndrome defined by Blake et al by presenting with three major criteria: choanal atresia, characteristic ear abnormalities and cranial nerve dysfunction, and four minor criteria: developmental delay, growth deficiency, an orofacial cleft and genital hypoplasia

Summary

INTRODUCTION

CHARGE syndrome (OMIM #214800) is an autosomal dominant genetic disorder that was first reported in Pagon et al (1981). We report a patient clinically diagnosed with typical CHARGE syndrome that fulfilled both Blake and Verloes criteria (Blake et al, 1998; Verloes, 2005), but who was genetically diagnosed with atypical KS based on the presence of a de novo KMT2D mutation and the absence of pathogenic variation in CHD7. This case demonstrates the phenotypic overlap between CHARGE syndrome and KS. A microarray-based comparative genomic hybridization assay revealed no obvious pathogenic DNA copy number aberrations

MATERIALS AND METHODS

DISCUSSION

Findings

ETHICS STATEMENT