Molecular characteristics
Biallelic GPSM2 variants were initially discovered through homozygosity mapping and exome sequencing in people with profound congenital deafness and brain malformations detected with magnetic resonance imaging (MRI), including frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a diagnosis of Chudley-McCullough syndrome.
GPSM2 is located on chromosome 1p13 band. Disease-causing variants are inactivating the G protein signaling modulator 2, which maintains inner hair cell polarity and spindle orientation. The clinical features of CMCS are attributed to asymmetric cell divisions in both the inner ear and the brain during development.
Pathogenic variants in GPSM2 seem to be highly specific of Chudley-McCullough syndrome and have not been reported in association with any other brain malformation or neurodevelopmental disease. No other genes are known to cause the condition. There are currently no apparent genotype/phenotype correlations. There has been no reported evidence for triplosensitivity.
Suspected pathophysiologic mechanism
Disease-causing variants in G-protein signaling modulator 2 (GPSM2 in humans, also known as Leu-Gly-Asn repeat-enriched protein (LGN), mammalian Partner of inscuteable (mPins) or Gpsm2 in mammals) were found to cause CMCS. Gpsm2 defines an ~200 nm nanodomain at the tips of stereocilia via its interaction with the scaffold protein whirlin, myosin 15 and the α-subunit of the heterotrimeric G-protein Gi3. Loss-of-function GPSM2 variants affect actin-rich stereocilia elongation in epithelial and neuronal tissues.
Types of variants
There have been 22 reported cases of CMCS with eight different variants in GPSM2 identified. These pathogenic variants are nonsense, frameshift or missense variants. Pathogenic variants are distributed along the entire coding sequence, and no protein domain is particularly affected. Other mechanisms such as gene deletions are in principle possible.
Diagnostic testing
The diagnosis of Chudley-McCullough syndrome may be suspected with characteristics of hearing loss and neuroimaging detecting brain anomalies of the corpus callosum. Molecular genetic testing is used to confirm the diagnosis. Considering neurological manifestations may be subtle or absent, it is important to include GPSM2 in the molecular testing of non-syndromic hearing loss. Targeted sequence analysis of the GPSM2 coding region or exome/genome sequencing identify biallelic pathogenic variants.
GPSM2