Table 1.

Molecular Genetic Testing Used in Disorders of GNAS Inactivation

Gene 1MethodProportion of Probands with a Diagnostic Change 2 Detectable by Method
GNAS Sequence analysis 362%-82% 4
Gene-targeted deletion/duplication analysis 510 deletions reported to date 6
Methylation analysis 710%-60% (virtually 100% for PHP-Ib) 4
Chromosomal microarray analysis 810% 9
STX16 Gene-targeted deletion/duplication analysis 5See footnote 10.
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Includes: two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and postnatal growth restriction and clinical manifestations suggestive of PPHP [Geneviève et al 2005]; a female with PHP-Ia and a 30-kb deletion (including GNAS exons 1-5) inherited from her mother, who was mosaic for this heterozygous deletion [Fernandez-Rebollo et al 2010]; brothers with PHP-Ia and an 850-kb deletion (involving all of GNAS as well as other genes) that was inherited from their mother, who had PPHP [Mitsui et al 2012]; and seven novel genomic deletions ranging from 106 bp to 2.6 Mb in families with PHP-Ia [Garin et al 2015]

7.

Methylation analysis examines differentially methylated regions (DMRs) of the GNAS complex locus for loss of the normal methylation pattern on the maternal allele.

8.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the GNAS complex locus/STX16 region. Note: The GNAS complex locus/STX16 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms.

9.
10.

Relevant for testing those with the PHP-Ib phenotype who: do not have an identified maternal GNAS pathogenic variant; and do have a methylation defect at exon A/B DMR (also referred to as exon 1A or GNAS A/B:TSS-DMR)

From: Disorders of GNAS Inactivation

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