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.

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome

“…In an infant male with a micropenis or undescended testes, a magnetic resonance image (MRI) can be used as a primary diagnostic method . MRI in subjects with WS and SOX10 pathogenic variants frequently reveals hypoplasia or aplasia of the olfactory bulbs; in addition, inner ear or temporal bone abnormalities are often present . In older children, an MRI is often unnecessary and formal testing for anosmia or hyposomia can establish the diagnosis of Kallmann's syndrome .…”

“…method 53,54. MRI in subjects with WS and SOX10 pathogenic variants frequently reveals hypoplasia or aplasia of the olfactory bulbs; in addition, inner ear or temporal bone abnormalities are often present [55][56][57][58][59][60][61][62][63][64][65][66][67]. In older children, an MRI is often unnecessary and formal testing for anosmia or hyposomia can establish the diagnosis of Kallmann's syndrome 68.…”

Novel EYA1 variants causing Branchio-oto-renal syndrome

“…Variants were called and filtered using online software as previously described [8]. CoNIFER (Copy Number Inference From Exome Reads) was used to identify CNVs from whole exome sequencing (WES) data [9].…”

Novel pathogenic variants underlie SLC26A4 -related hearing loss in a multiethnic cohort

“…WES and Sanger sequencing was performed using our previously reported protocol [8, 9]. Polyphen2, SIFT and MutationTaster were used for in silico analysis, GERP and Phastcons scores were used to evaluate the conservation of the variants.…”