Molecular (SNP) analyses of overlapping hemizygous deletions of 10q25.3 to 10qter in four patients: Evidence for HMX2 and HMX3 as candidate genes in hearing and vestibular function

Abstract

We report on the analyses of four unrelated patients with de novo, overlapping, hemizygous deletions of the long arm of chromosome 10. These include two small terminal deletions (10q26.2 to 10qter), a larger terminal deletion (10q26.12 to 10qter), and an interstitial deletion (10q25.3q26.13). Single nucleotide polymorphism (SNP) studies (Illumina 550 K) established that these deletions resulted in the hemizygous loss of ∼6.1, ∼6.1, ∼12.5, and ∼7.0 Mb respectively. Additionally, these data establish that Patients 1, 2, and 3 share common, distal, hemizygous deleted regions of 6.09 Mb containing 37 RefSeq genes. Patients 3 and 4 share a 2.52 Mb deleted region corresponding to the proximal deleted region of Patient 3 and the distal deleted region of Patient 4. This common, hemizygous region contains 20 RefSeq genes including two H6 family homeobox genes (HMX2 and HMX3). Based on previous reports that Hmx2/Hmx3 knockout mice have vestibular anomalies, we propose that hemizygous deletions of HMX2 and HMX3 are responsible for the inner ear malformations observed from CT images, vestibular dysfunction, and congenital sensorineural hearing loss found in Patients 3 and 4.

Karyotype-Phenotype Correlation in Partial Trisomies of the Short Arm of Chromosome 6: A Family Case Report and Review of the Literature

“…HMX2 and HMX3 are coexpressed in the dorsolateral otic epithelium to temporally and spatially signal the embryonic transition of the pars superior of the otocyst to a fully developed vestibular system. These genes are also expressed in the developing central nervous system, including the neural tube and hypothalamus [Miller et al, 2009]. Nevertheless, in the present study, the father's vestibular complaint could be related to Arnold-Chiari malformation type I; additionally, MRI and CT scans showed normal inner ear structures.…”

“…They are strong candidate genes for human inner ear development, and they could have a role in sensorineural hearing and vestibular balance disorders [Miller et al, 2009]. The inner ear develops from a placode of ectoderm known as the otic placode.…”

Molecular and clinical analyses with neuropsychological assessment of a case of del(10)(q26.2qter) without intellectual disability: Genomic and transcriptomic combined approach and review of the literature

“…Frequent findings of individuals with subtelomeric deletion 10q (present in !50%), include low birthweight, microcephaly at birth, short stature in childhood/adulthood, characteristic facial dysmorphism, intellectual disability, and behavioral problems (summed up for 21 patients of the literature in Table I) [Irving et al, 2003;Courtens et al, 2006;Miller et al, 2009;Yatsenko et al, 2009;Iourov et al, 2014] . On the basis of genomics arrays data, previous efforts to establish genotype-phenotype correlations proposed a 600 kb minimal critical region encompassing the C10orf90 and DOCK1 genes.…”

“…Common clinical findings include psychomotor delay/ intellectual disability with hypotonia, pre-and post-natal growth retardation, congenital heart disease, genital/ urinary tract anomalies, microcephaly, and mild facial dysmorphism [Courtens et al, 2006]. We decided to focus our interest on the subtelomeric deletion 10q26 (clinical data summed up for 21 patients of the literature in Table I) [Irving et al, 2003;Courtens et al, 2006;Miller et al, 2009;Yatsenko et al, 2009;Iourov et al, 2014]. On a molecular level, the haploinsufficiency of the DOCK1, C10orf90, and CALY genes have been discussed as …”

Novel interstitial deletion of 10q24.3–25.1 associated with multiple congenital anomalies including lobar holoprosencephaly, cleft lip and palate, and hypoplastic kidneys

“…Deletions on the long arm of chromosome 10 vary in size and location, and present with diverse phenotypic features [Miller et al, 2009]. Deletions of the distal end of 10q have been associated with common characteristics, such as dysmorphic facial features, intellectual disability, hypotonia, growth retardation, congenital heart disease, and urogenital abnormalities [Irving et al, 2003], although there is significant clinical variability between patients.…”