Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2021 Sep;29(9):1384-1395.
doi: 10.1038/s41431-021-00818-9. Epub 2021 Feb 16.

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K+ channelopathies

Karen W Gripp  1 , Sarah F Smithson  2 , Ingrid J Scurr  2 , Julia Baptista  3   4 , Anirban Majumdar  5 , Germaine Pierre  6 , Maggie Williams  7 , Lindsay B Henderson  8 , Ingrid M Wentzensen  8 , Heather McLaughlin  9 , Lisette Leeuwen  10 , Marleen E H Simon  11 , Ellen van Binsbergen  11 , Mary Beth P Dinulos  12 , Julie D Kaplan  1 , Anne McRae  13 , Andrea Superti-Furga  14 , Jean-Marc Good  14 , Kerstin Kutsche  15
Affiliations
Case Reports

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K+ channelopathies

Karen W Gripp et al. Eur J Hum Genet. 2021 Sep.

Abstract

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.

PubMed Disclaimer

Conflict of interest statement

KWG is the CMO for FDNA, the company providing the Face2Gene application. IMW and LBH are employees of GeneDx, Inc. HM is an employee and shareholder at Invitae Corporation. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Facial photographs from 20 individuals with a pathogenic KCNH1 variant.
The facial photos are arranged in order of age from youngest to oldest. The five newly reported patients are indicated by P1–P5. Note the hypotonic facial expression, with open mouth posture and inverted V-shape of the upper lip, and apparent ptosis in some individuals. Facial shape elongates with age (third row), but myopathic facial features remain. a, b Patient 3 (P3; at age 16 months) and patient 4 (P4; at age 1 year 7 months) reported in this study (described in detail in Table 1). c Patient at age 3 years reported in [17] (with permission from Springer Nature). d Patient at age 4 years reported in [48] (with permission from John Wiley and Sons). e Patient at age 4 years 4 months reported in [18] (with permission from Springer Nature). f Patient at age 3 years 7 months reported in [49] (with permission from John Wiley and Sons). g Patient at age 6 years reported in [17] (with permission from Springer Nature). h Patient at age 6 years reported in [17] (with permission from Springer Nature). i Patient at age 6 years 10 months reported in [50] (with permission from Wiley and Sons). j Patient at age 7 years reported in [14]. k Patient at age 8 years reported in [17] (with permission from Springer Nature). l Patient at age 9 years reported in [16]. m Patient 2 (P2; at age 9 years) reported in this study (described in detail in Table 1) and previously reported in [18] (individual 3). n Patient at age 12 years reported in [14]. o Patient at age 13 years reported in [18] (with permission from Springer Nature). p Patient at age 12 years 8 months reported in [14]. q Patient at age 14 years reported in [18] (with permission from Springer Nature). r Patient (age unknown) reported in [14]. s Patient 1 (P1; at age 14 years) reported in this study (described in detail in Table 1). t Patient 5 (P5; at age 34 years) reported in this study (described in detail in Table 1). u, v Fingers of patient 3 (P3; at age 16 months; as described in detail in Table 1), showing proximally placed hypoplastic thumbs with hypoplastic nails. w, x Toes of Patient 3 (P3; at age 14 months; as described in detail in Table 1), showing anonychia of toes 1 and 2 and hypoplastic nails on toes 3–5. y, z Toes of patient 4 (P4; at age 3 years 10 months; as described in detail in Table 1), showing elongated toes with hypoplastic nails.
Fig. 2
Fig. 2. Photographs from six individuals with a pathogenic KCNN3 variant.
The three newly reported patients are indicated by P6–P8. Note the broad nasal tip, wide mouth, and coarse facial features. Same patient as child (a; at age 5 years) and as adult (b; at age 46 years) after cosmetic facial surgery (previously published in [23]). c, d Two additional individuals, both aged 5 years, previously reported in [23]. e Facial photograph of patient 6 (P6; at age 19 months) reported here (see Table 1 for details) showing epicanthal folds, with distal digital hypoplasia with hypoplastic finger nails (f). g Facial photograph of patient 7 (P7; at age 9 years) reported here (see Table 1 for details), with hypoplastic finger nails (h). i Facial photograph of patient 8 (P8; at age 30 years) reported here (see Table 1 for details), showing full lower lip, with hypoplastic toe nails (j) and hypoplastic finger nails (k).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Anderson PA, Greenberg RM. Phylogeny of ion channels: clues to structure and function. Comp Biochem Physiol B Biochem Mol Biol. 2001;129:17–28. doi: 10.1016/S1096-4959(01)00376-1. - DOI - PubMed
    1. Niday Z, Tzingounis AV. Potassium channel gain of function in epilepsy: an unresolved paradox. Neuroscientist. 2018;24:368–80. doi: 10.1177/1073858418763752. - DOI - PMC - PubMed
    1. Bauer CK, Schwarz JR. Ether-a-go-go K(+) channels: effective modulators of neuronal excitability. J Physiol. 2018;596:769–83. doi: 10.1113/JP275477. - DOI - PMC - PubMed
    1. Kohling R, Wolfart J. Potassium channels in epilepsy. Cold Spring Harb Perspect Med. 2016;6:a022871. doi: 10.1101/cshperspect.a022871. - DOI - PMC - PubMed
    1. Allen NM, Weckhuysen S, Gorman K, King MD, Lerche H. Genetic potassium channel-associated epilepsies: Clinical review of the Kv family. Eur J Paediatr Neurol. 2020;24:105–16. doi: 10.1016/j.ejpn.2019.12.002. - DOI - PubMed

Publication types

MeSH terms

Substances

Supplementary concepts