Pituitary hormone deficiency

Gene: KCNQ1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 4 Dec 2024, 11:37 a.m. | Last Modified: 4 Dec 2024, 11:37 a.m.

Panel Version: 3.14

Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously identified variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.

Created: 14 Feb 2024, 1:04 p.m. | Last Modified: 14 Feb 2024, 1:04 p.m.

Panel Version: 3.8

As reviewed by Suzanne Page, PMID:36077086 reports two unrelated cases with KCNQ1 variants in addition to the cases previously reported in PMID: 29097701 with pituitary hormone deficiency and maternally inherited gingival fibromatosis. The single individual reported in PMID:36077086 with p.Pro369Leu variant had growth hormone deficiency and postnatal growth retardation in addition to coarse facial features and early-onset gingival overgrowth. However, three members of the other family with p.Val185Met variant had only coarse facial features and early-onset gingival overgrowth.

Created: 14 Feb 2024, 1:03 p.m. | Last Modified: 14 Feb 2024, 1:03 p.m.

Panel Version: 3.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 36077086

Green List (high evidence)

Bauer et al 2022 PMID: 36077086 - Identified a single individual with the KCNQ1 variant P369L and three family members with the V185M variant. All had gingival overgrowth. Tommiska et al 2017 (PMID: 29097701) have already identified 3 families affected with pituitary hormone deficiency and maternally inherited gingival fibromatosis. Bauer et al showed that all 3 variants impaired Ca2+ sensitivity of the mutant KCNQ1 channels. With low Ca2+, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component. They suggest that the impaired Ca2+ sensitivity of the KCNQ1 mutant channels R116L, V185M and P369L is causally related to their gain-of-function when forming heteromers with KCNE2.

Created: 9 Feb 2024, 4:51 p.m. | Last Modified: 9 Feb 2024, 4:55 p.m.

Panel Version: 3.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Gingival overgrowth; with or without postnatal growth retardation

Publications

• 36077086

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

No new evidence reported since the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group at that point agreed that there is insufficient evidence to rate this gene as green. Therefore leaving this gene amber for now.

Created: 17 Sep 2022, 5:09 p.m. | Last Modified: 17 Sep 2022, 5:09 p.m.

Panel Version: 2.50

Review on behalf of Professor Mehul Dattani, UCL GOS Institute of Child Health/Great Ormond Street Hospital for Children. Tommiska J, Knskoski J, Skibsbye L, Vaaralahti K, Liu X, Lodge EJ, Tang C, Yuan L, Fagerholm R, Kanters JK, Lahermo P, Kaunisto M, Keski-Filppula R, Vuoristo S, Pulli K, Ebeling T, Valanne L, Sankila EM, Kivirikko S, Lperi M, Casoni F, Giacobini P, Phan-Hug F, Buki T, Tena-Sempere M, Pitteloud N, Veijola R, Lipsanen-Nyman M, Kaunisto K, Mollard P, Andoniadou CL, Hirsch JA, Varjosalo M, Jespersen T, Raivio T.Nat Commun. 2017 Nov 3;8(1):1289. doi: 10.1038/s41467-017-01429-z.PMID:29097701

Created: 14 Sep 2022, 4:44 p.m. | Last Modified: 14 Sep 2022, 4:44 p.m.

Panel Version: 2.15

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Maternally inherited gingival fibromatosis

Publications

• 29097701

Green List (high evidence)

Tommiska et al 2017 (PMID: 29097701) - three unrelated families with pituitary hormone deficiency and maternally inherited gingival fibromatosis. p.(Arg116Leu) variant co-segregates with the disorder in one family (14 meiosis). p.(Pro369Leu) variant identified in 2 unrelated families, co-segregated in 1 family, proband only test tested in second family. Mechanism by which the two KCNQ1 mutations cause pituitary hormone deficiency in humans is unclear but authors propose involvement of KCNQ1KCNE2 complex.

Created: 16 Jan 2019, 1:27 p.m.

Publications

• 29097701

Comment on list classification: Comment on list classification: As discussed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group agreed that there is insufficient evidence to rate this gene as green. So demoted from green to amber.

Created: 29 Jan 2019, 11:56 a.m.

Comment on list classification: Promoted from green to amber as recommended by Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust).

Created: 17 Jan 2019, 10:29 a.m.

Comment on list classification: Demoted from green to amber based on literature evidence. KCNQ1 is not associated with pituitary hormone deficiency in OMIM or Gene2Phenotype. PMID: 29097701 found that 3 unrelated families (2 Finnish and 1 Argentinian) with pituitary hormone deficiency and maternally inherited gingival fibromatosis have missense variants in the KCNQ1 gene.

Created: 10 Dec 2018, 11:59 a.m.