Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| HUSP Clinical Genetics Laboratory, |
RCV001376073 | SCV001572895 | likely pathogenic | Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type I A | 2020-11-09 | no assertion criteria provided | clinical testing | The variant was detected in a 13-years-old boy with short stature and hypothyroidism. The c.403_411delATGAACGTG variant in the GNAS gene (NM_000516.7) is a deletion of nine nucleotides of exon 5. This alteration has not been reported previously in the literature and it is not detected in general population. Pathological variants in the GNAS gene have been associated with the following phenotypes: Pseudopseudohypoparathyroidism (OMIM 612463), Pseudohypoparathyroidism Ia (OMIM 103580), Pseudohypoparathyroidism Ib (OMIM 603233), Pseudohypoparathyroidism Ic (OMIM 612462) and Progesive bone heteroplasia (OMIM 166350), following a mode of inheritance autosomal dominant with imprinting. A genetic study has been carried out in the parents and it is determined that none of them presents the variant c.403_411delATGAACGTG in the GNAS gene, so it appears de novo in our patient. This fact encourages the reported variant to be considered as pathological. In order to correctly classify Albright's osteodystrophy in our patient, using sequencing of the region involved in the parents we have been able to determine that it is on the chromosome of maternal origin. Pathological variants in the GNAS gene of origin maternal (therefore subjected to maternal imprinting) are associated with the phenotypes of Pseudohypoparathyroidism Ia (OMIM 103580) or Pseudohypoparathyroidism Ic (OMIM 612462). Both entities are clinically identical: Albright hereditary osteodystrophy phenotype, hypocalcaemia, hyperphosphataemia, resistance to various hormones (PTH with normal renal function, TSH, GH). They only differ in Pseudohypoparathyroidism Ia shows a decrease in Gs-alpha protein levels in cell membranes. Our patient has a 50% risk of transmitting the pathological variant to her offspring. As she is a woman, in case any descendant receives the pathological variant is expected to present symptoms of Pseudohypoparathyroidism Ia or Pseudohypoparathyroidism Ic. |