A Splice‐Region Variant Causes an Atypical Presentation of <scp>GNAS</scp> Inactivation Disorder

Pathogenic variants in GNAS can cause a wide range of diseases including pseudohypoparathyroidism, pseudopseudohypoparathyroidism, McCune-Albright syndrome, among others. The specific phenotypic features that may be seen are influenced by the variant type and location in the gene, whether it causes loss or gain of function, and whether it is germline or somatic in nature. The GNAS locus is imprinted, which also results in a parent-of-origin effect. Typically, germline loss of function variants on the maternal allele are associated with variable hormonal resistances, obesity, intrauterine growth restriction, and cognitive impairment. Here, we describe a mother and daughter with a unique splicing variant near exon 5 of the GNAS gene (NM_000516.5:c.432 + 5G>A), shown to cause alternative splicing through RNA sequencing (RNA-seq), likely resulting in a loss-of-function effect. Segregation testing revealed that the variant arose de novo in the mother, and phasing showed it was on her paternal allele. The resultant phenotype includes a SHOX deficiency-like disorder with Madelung deformity in the mother, and significant growth restriction with brachydactyly in the daughter, further expanding the phenotypic spectrum of GNAS inactivation disorders.