Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss

Abstract

The genetics of both syndromic (SHL) and non-syndromic hearing loss (NSHL) is characterized by a high degree of genetic heterogeneity. We analyzed whole exome sequencing data of 102 unrelated probands with apparently NSHL without a causative variant in known NSHL genes. We detected five causative variants in different SHL genes (SOX10, MITF, PTPN11, CHD7, and KMT2D) in five (4.9%) probands. Clinical re-evaluation of these probands shows that some of them have subtle syndromic findings, while none of them meets clinical criteria for the diagnosis of the associated syndrome (Waardenburg (SOX10 and MITF), Kallmann (CHD7 and SOX10), Noonan/LEOPARD (PTPN11), CHARGE (CHD7), or Kabuki (KMT2D). This study demonstrates that individuals who are evaluated for NSHL can have pathogenic variants in SHL genes that are not usually considered for etiologic studies.

Figure 1. Pedigrees and electropherograms of five families with a causative DNA variant and craniofacial appearance of probands 694, 713, and 859.

Black squares and circles denote affected males and females with hearing loss, respectively. Proband 694 has a square face with prominent nasal bridge and columella. Other facial features of CHARGE syndrome such as facial palsy or outer ear findings are missing. Proband 713 has hypertelorism and slightly low-set, posteriorly rotated ears. Other facial features of Noonan/LEOPARD syndrome such as epicanthal folds or ptosis is missing. Proband 859 shows telechantus, epicanthal folds, slightly downslanting palpebral fissures with short columella. Facial features of Kabuki syndrome including long palpebral fissures with eversion of the lateral lower eyelid, arched and broad eyebrows with the lateral third displaying sparseness, and large or prominent ears are missing.