The relationship between SMPX and X-linked nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 9/8/17. Variants in SMPX were first reported in humans with the disease as early as 2011 (Schraders et al., 21549342). At least six variants, nonsense and frameshift, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported at least 8 probands in 5 publications (21549342, 21549336, 21893181, 22911656, 28542515). Variants in this gene segregated with disease in >100 additional family members. The families studied display an expected-X linked inheritance pattern where the hearing loss is earlier onset and more profound in males and slightly less penetrant in females. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by expression studies. Loss of function of SMPX is expected to impact the ability of inner ear hair cells to conduct sound. It is important to note that there were SMPX null mice generated to investigate the effect of the deletion on muscle organization and function, however hearing loss was not studied in these mice (Palmer et al. 2001). In summary, SMPX is definitively associated with X-linked nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 9/12/17.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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