Background

Childhood hearing impairment affects language and cognitive development. Profound congenital sensorineural hearing impairment can be due to an abnormal cochleovestibular nerve (CVN) and cochleovestibular malformations, however, the etiology of these conditions remains unclear.

Methods

We used a trio-based exome sequencing approach to unravel the underlying molecular etiology of a child with a rare nonsyndromic CVN abnormality and cochlear hypoplasia. Clinical and imaging data were also reviewed.

Results

We identified a de novo missense variant [p(Asn174Tyr)] in the DNA-binding Homeodomain of SIX1, a gene which previously has been associated with autosomal dominant hearing loss (ADHL) and branchio-oto-renal or Branchio-otic syndrome, a condition not seen in this patient.

Conclusions

SIX1 has an important function in otic vesicle patterning during embryogenesis, and mice show several abnormalities to their inner ear including loss of inner ear innervation. Previous reports on patients with SIX1 variants lack imaging data and nonsyndromic AD cases were reported to have no inner ear malformations. In conclusion, we show that a de novo variant in SIX1 in a patient with sensorineural hearing loss leads to cochleovestibular malformations and abnormalities of the CVN, without any other abnormalities. Without proper interventions, severe to profound hearing loss is devastating to both education and social integration. Choosing the correct intervention can be challenging and a molecular diagnosis may adjust intervention and improve outcomes, especially for rare cases.

Background

Necrotizing meningoencephalitis (NME, aka Pug dog encephalitis) is an inflammatory brain condition associated with advanced disease at initial presentation, rapid progression, and poor response to conventional immunomodulatory therapy.

Hypothesis/objectives

That genetic risk for NME, defined by a common germline DNA haplotype located on chromosome 12, is associated with altered blood cytokine concentrations and leukocyte subsets in asymptomatic Pugs.

Animals

Forty Pug dogs asymptomatic for NME from a hospital sample.

Methods

Prospective observational cohort study, including germline genome-wide genotyping, plasma cytokine determination by multiplexed profiling, and leukocyte subset characterization by flow cytometric analysis.

Results

Seven (18%) dogs were high risk, 10 (25%) medium risk, and 23 (58%) low risk for NME, giving a risk haplotype frequency of 30%. High and medium risk Pugs had significantly lower proportion of CD4+ T cells (median 22% [range, 7.3%-38%] vs 29% [range, 16%-41%], P = .03) and higher plasma IL-10 concentrations than low-risk Pugs (median 14.11 pg/mL [range, 9.66-344.19 pg/mL] vs 12.21 pg/mL [range, 2.59-18.53 pg/mL], P = .001). No other variables were significantly associated with the NME haplotype-based risk.

Conclusions and clinical importance

These data suggest an immunological underpinning to NME and a biologic rationale for future clinical trials that investigate novel diagnostic, preventative, and therapeutic strategies for this disease.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.