Seizures, Cortical Blindness, Microcephaly Syndrome and Deafness, Autosomal Dominant 1 (DFNA1) via the DIAPH1 Gene

Nonsyndromic hearing loss is characterized by difficulty or inability to hear that is not associated with any visible defects involving the external ear, other organs, or any other medical condition. Nonsyndromic hearing loss may be associated with abnormalities involving the middle ear and/or the inner ear (Ciuman 2013; Dodson et al. 2011; Hilgert et al. 2009). At least 70% of cases involving hearing loss are nonsyndromic (Van Camp et al. 1997).

Nonsyndromic hearing loss and deafness due to pathogenic variants in the DIAPH1 gene involves autosomal dominant, fully penetrant, low-frequency deafness beginning at about 10 years of age and progressing to profound bilateral deafness involving all frequencies by 30 years of age (Lynch et al. 1997; Sloan-Heggen et al. 2016).

Pathogenic variants in DIAPH1 are also associated with seizures, cortical blindness, and microcephaly syndrome, an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, developmental delay, brain abnormalities and cortical blindness. Affected individuals may also show facial dysmorphism and overall poor growth with short stature, although hearing is normal (Al-Maawali et al. 2016; Ercan-Sencicek et al. 2015; Yavarna et al. 2015).

The DIAPH1 gene is located on chromosome 5q31, spanning 108 kb and consisting of 28 coding exons that produce a 1272 amino acid protein. The DIAPH1 protein is ubiquitously expressed throughout the body, including the cochlea and brain, and is involved in actin polymerization and microtubule stabilization (Lynch et al. 1997; Ercan-Sencicek et al. 2015; Pan et al. 2014; Lin et al. 2015).

Pathogenic variants in DIAPH1 for nonsyndromic hearing loss are inherited in an autosomal dominant manner. Only one splicing variant thought to lead to partial loss of function and one missense variant have been described as pathogenic for DFNA1 (Lynch et al. 1997; Sloan-Heggen et al. 2016).

Pathogenic variants in DIAPH1 for seizures, cortical blindness, and microcephaly syndrome are inherited in an autosomal recessive manner. Only three nonsense variants have been reported as pathogenic for seizures, cortical blindness, and microcephaly syndrome (Al-Maawali et al. 2016; Ercan-Sencicek et al. 2015; Yavarna et al. 2015).

The clinical sensitivity of this sequencing test is not precisely known. In a study of 1,119 patients with hearing loss in which 440 patients received a genetic diagnosis, only one pathogenic variant in DIAPH1 was detected (Sloan-Heggen et al. 2016). Only three nonsense variants have been reported as pathogenic for seizures, cortical blindness, and microcephaly syndrome (Al-Maawali et al. 2016; Ercan-Sencicek et al. 2015; Yavarna et al. 2015). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

In 79 patients with a clinical diagnosis of sensorineural hearing loss 15 deletion/duplication variants in DIAPH1 were detected (Ji et al. 2014). However, the pathogenicity of these variants was not fully evaluated and they were of a size (~100-150 bp) more likely to be detected by sequencing. No large deletion or duplication variants associated with DIAPH1 have been reported as pathogenic for seizures, cortical blindness, and microcephaly syndrome.

This test provides full coverage of all coding exons of the DIAPH1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.