Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion

Abstract

Preferential transmission of a genetic mutation to the next generation, referred to as transmission ratio distortion (TRD), is well established for several dominant disorders, but underlying mechanisms remain undefined. Recently, TRD was reported for patients affected by pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism. To determine whether TRD is observed also for autosomal dominant pseudohypoparathyroidism type Ib (AD‐PHP1B), we analyzed kindreds with the frequent 3‐kb STX16 deletion or other STX16/GNAS mutations. If inherited from a female, these genetic defects lead to loss‐of‐methylation at exon A/B alone or at all three differentially methylated regions (DMR), resulting in parathyroid hormone (PTH)‐resistant hypocalcemia and hyperphosphatemia and possibly resistance to other hormones. In total, we investigated 212 children born to 80 females who are unaffected carriers of a STX16/GNAS mutation (n = 47) or affected by PHP1B (n = 33). Of these offspring, 134 (63.2%) had inherited the genetic defect (p = .00012). TRD was indistinguishable for mothers with a STX16/GNAS mutation on their paternal (unaffected carriers) or maternal allele (affected). The mechanisms favoring transmission of the mutant allele remain undefined but are likely to include abnormalities in oocyte maturation. Search for mutations in available descendants of males revealed marginally significant evidence for TRD (p = .038), but these analyses are less reliable because many more offspring of males than females with a STX16/GNAS mutation were lost to follow‐up (31 of 98 versus 6 of 218). This difference in follow‐up is probably related to the fact that inheritance of a mutation from a male does not have clinical implications, whereas inheritance from an affected or unaffected female results in PHP1B. Lastly, affected PHP1B females had fewer descendants than unaffected carriers, but it remains unclear whether abnormal oocyte development or impaired actions of reproductive hormones are responsible. Our findings highlight previously not recognized aspects of AD‐PHP1B that are likely to have implications for genetic testing and counseling. © 2020 American Society for Bone and Mineral Research (ASBMR).

Molecular Definition of Pseudohypoparathyroidism Variants

“…Furthermore, females affected by PHP1A or PPHP ( 118 ) preferentially transmit the mutant GNAS allele to the next generation. Similar transmission ratio distortion is observed for females who are carriers of STX16 or GNAS mutations that cause AD-PHP1B when located on the maternal allele ( 119 ). In addition, females affected by AD-PHP1B due to a maternal mutation have significantly fewer offspring than unaffected females, who carry these mutations on their paternal allele.…”

Genetics of monogenic disorders of calcium and bone metabolism

“…4,5 There may also be the preferential transmission of the mutant allele (i.e., transmission ratio distortion) as reported for mother-to-offspring transmission of PHP1A-associated GNAS and pseudohypoparathyroidism type 1B (PHP1B)-associated Syntaxin 16 (STX16) gene mutations. 6,7 Monogenic disorders may arise in the absence of relevant family history; for example, McCune-Albright syndrome arises from a postzygotic somatic GNAS mutation in early embryonic development 8,9 ; while many disorders may be associated with de novo germline mutations (e.g., ~10% of index cases with MEN1). 10,11 The majority of monogenic disorders arise from genetic variation affecting the coding region of the responsible gene to alter gene function (e.g., gain or loss of function).…”

“…Parent‐of‐origin effects may also occur due to genomic imprinting; for example, maternally inherited inactivating GNAS mutations, which encodes the G‐protein alpha subunit (Gαs), cause pseudohypoparathyroidism type 1A (PHP1A)/Albright's hereditary osteodystrophy (AHO), while the equivalent paternally inherited mutations cause AHO without accompanying endocrine manifestations (e.g., pseudopseudohypoparathyroidism [PPHP]) 4,5 . There may also be the preferential transmission of the mutant allele (i.e., transmission ratio distortion) as reported for mother‐to‐offspring transmission of PHP1A‐associated GNAS and pseudohypoparathyroidism type 1B (PHP1B)‐associated Syntaxin 16 (STX16) gene mutations 6,7 . Monogenic disorders may arise in the absence of relevant family history; for example, McCune–Albright syndrome arises from a postzygotic somatic GNAS mutation in early embryonic development 8,9 ; while many disorders may be associated with de novo germline mutations (e.g., ~10% of index cases with MEN1) 10,11 …”