Whole‐genome sequencing revealed a novel long‐range deletion mutation spanning GNAS in familial pseudohypoparathyroidism

Background Pseudohypoparathyroidism (PHP) is a series of diseases related to pathological changes and neurocognitive and endocrine abnormalities, mainly due to the GNAS mutation on chromosome 20q13.2, which weakens receptor‐mediated hormone signal transduction. Considering its complex genetic and epigenetic characteristics, GNAS may produce complex clinical phenotypes in families or sporadic cases. This study presented a case of familial PHP caused by a deletion mutation in the 20q13.2 region. Methods and Results The proband and her second daughter had PHP, and the proband's mother had pseudo‐PHP. Whole‐genome sequencing revealed that the proband had an 849.81 kb deletion spanning GNAS near the maternal 20q13.2 chromosome. Multiplex ligation‐dependent probe amplification methylation analysis indicated that the proband as well as her mother and second daughter had seemingly abnormal GNAS methylation. This is different from the phenotype (feeding difficulty, slow growth, and special facial features) of previously reported cases with the deletion of fragments near the 20q13.2 chromosome. Conclusions This report demonstrated the variability of 20q13.2 deletion phenotypes and the clinical importance of using multiple molecular genetic detection methods. Pseudohypoparathyroidism (PHP) and related diseases are associated with a series of pathological changes, neurocognitive, and endocrine abnormalities, mainly due to the GNAS mutation on chromosome 20q13.2, which leads to the weakening of receptor‐mediated hormone signal transduction. Because GNAS has complex genetic and epigenetic characteristics, it may produce more complex clinical phenotypes of family or sporadic cases. Here, we introduce family cases of three generations in China. The proband and her youngest daughter showed moon‐face, short stature, hormone resistance, and Albright hereditary osteodystrophy. The mother of the proband showed pseudo‐pseudohypoparathyroidism phenotype. This is different from the phenotype (feeding difficulty, slow growth, and special facial features) of the previously reported cases with deletion of fragments near 20q13.2.