April 25, 2024

Identification of a Novel GNAS Mutation in a Family with Pseudohypoparathyroidism Type 1A

Fabio Sippelli, Silvana Briuglia, Chiara Ferraloro, Anna Paola Capra, Emanuele Agolini, Tiziana Abbate, Giorgia Pepe, Tommaso Aversa, Malgorzata Wasniewska & Domenico Corica

Pseudohypoparathyroidism (PHP) encompasses genetic diseases marked by unresponsiveness to parathyroid hormone due to GNAS gene causative variants or epigenetic changes. PHP manifests hormonal resistance, Albright hereditary osteodystrophy (AHO) traits, and obesity in some cases. Five PHP subtypes exist, varying in genetic origins and clinical features, such as PTH and TSH resistance. Over 180 GNAS mutations causing PHP1A are known, with unpredictable genotype-phenotype correlations due to complex GNAS locus dynamics. This study described novel GNAS mutation in a PHP1A family, and highlighted phenotypic diversity among affected members despite shared genetic mutation.

Novel GNAS Mutation Identified in Pseudohypoparathyroidism Type 1A Family

The authors described PHP1A family with 4 affected members sharing the identical GNAS gene mutation but displaying varied phenotypic presentations. The mother exhibited mild PHP1A signs, notably less severe than her daughters. Clinical features varied among the sisters: first showed progressive growth impairment and obesity, second had regular stature growth and obesity, and third had substantial short stature and obesity from childhood. Sisters displayed differing hormonal patterns, including hyperparathyroidism in all, congenital hypothyroidism in first and third, and later onset hypothyroidism in second.

Fig 1:

Pedigree of the described family.

The open symbols indicate pedigree members without PHP1A; the full black symbols, members with PHP1A

Exome Sequencing was conducted on a proband and her family members. The filtering and variants identification was carried out using Geneyx Analysis. The phenotyper of Geneyx, which correlates genes to phenotypes, enabled fast detection. This process revealed a novel variant (c.118_139+51del) in the GNAS gene. This variant, destroying canonical splice sites, was absent in the gnomAD and classified as likely pathogenic according to American College of Medical Genetics (ACMG) rules.


Significant Phenotypic Variability

In summary, three sisters with PHP1A and a novel maternally inherited GNAS mutation revealed significant clinical variations. The identified variant, a formerly unregistered GNAS mutation (c.118_139+51del) in heterozygous state confirmed the genetic cause of the disease. The study underscores the complexity of PHP1A’s genotype-phenotype variance and the importance of genetic counseling and thorough familial investigation for timely diagnosis and management.


Abbreviations for clinical words:

  1. Pseudohypoparathyroidism (PHP)
  2. Parathyroid hormone (PTH)
  3. Albright hereditary osteodystrophy (AHO)
  4. Thyroid-stimulating hormone (TSH)
  5. Growth hormone (GH)
  6. Hyperparathyroidism (no abbreviation)
  7. Congenital hypothyroidism (no abbreviation)
  8. Hypothyroidism (no abbreviation)
  9. Exome sequencing (ES)
  10. American College of Medical Genetics (ACMG)
  11. Combined Annotation-dependent Depletion (CADD)
  12. Sorting Intolerant from Tolerant (SIFT)
  13. Polymorphism Phenotyping v2 (PolyPhen-2)
  14. Genome Aggregation Database (gnomAD)


What types of genetic variants can Geneyx Analysis detect?




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