Chudley-Mccullough Syndrome (CMCS) and Deafness, Autosomal Recessive 82 (DFNB82) via the GPSM2 Gene

Chudley-McCullough syndrome (CMCS) is a neurologic disorder involving early-onset profound sensorineural hearing loss and in some patients, hydrocephalus. Additional brain malformations can be detected by MRI including partial agenesis of the corpus callosum, frontal polymicrogyria, gray matter heterotopia, cerebellar dysplasia, and arachnoid cysts (Doherty et al. 2012). Intellectual disability, seizures, abnormal psychomotor skills and dysmorphic features are uncommon features. Hearing loss may be congenital or rapidly progressive in infancy. Due to the absence of visible clinical features, this hearing loss disorder was originally classified as a nonsyndromic hearing loss, autosomal recessive deafness 82 (DFNB82). However, closer examination of DFNB82 individuals revealed brain abnormalities consistent with a diagnosis of CMCS (Doherty et al. 2012).

CMCS is an autosomal recessive disorder caused by pathogenic variants in the G-protein signaling modulator 2 (GPSM2) gene, which has been localized on chromosomal region 1p13.3 and contains 14 exons. Known causative variants for CMCS consist of six different nucleotide substitutions or single base pair deletions that all result in either nonsense, frameshift, or splicing variants. Two of these CMCS causative variants in GPSM2 were described in consanguineous Palestinian (Walsh et al. 2010) and Turkish families (Yariz et al. 2012) that were originally reported to have DFNB82. MRI scans revealed abnormalities consistent with CMCS in patients from both families (Doherty et al. 2012). Three of these CMCS causative variants in GPSM2 were described in either Mennonite individuals or individuals with Dutch or European ancestry (Doherty et al. 2012). The last of these six known CMCS causative variants in GPSM2 is a nucleotide substitution that disrupts the donor splice site of exon 9 and was found in a Mexican American family (Doherty et al. 2012). The GPSM2 protein is involved with modulating the activity of G-proteins, which transduce extracellular signals sensed by cell surface receptors into integrated cellular responses (Blumer et al. 2002). The GPSM2 protein (also called LGN due to 10 leu-gly-asn repeats) is expressed in a wide variety of tissues in the rat (Blumer et al. 2002). In the mouse, GPSM2 is expressed in the inner ear during embryonic development, and is localized to apical surfaces of hair cells and supporting cells (Walsh et al. 2010). The GPSM2 protein is thought to be involved in maintenance of cell polarity and spindle orientation in asymmetric cell division, but the exact function of this protein remains unknown.

In one study, all patients diagnosed with CMCS by brain imaging (n=12) were found to be homozygous for nonsense variants in GPSM2 (Doherty et al. 2012). In individuals with autosomal recessive nonsyndromic hearing loss that have not received a diagnosis of CMCS by brain imaging the clinical sensitivity of this test is difficult to predict because only a small number of patients have been reported. Analytical sensitivity should be high because all reported variants are detectable by sequencing.

This test provides full coverage of all coding exons of the GPSM2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).