Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

Abstract

BackgroundKCNH1 encodes a voltage-gated potassium channel that is predominantly expressed in the central nervous system. Mutations in this gene were recently found to be responsible for Temple-Baraitser Syndrome (TMBTS) and Zimmermann-Laband syndrome (ZLS).MethodsHere, we report a new case of TMBTS diagnosed in a Lebanese child. Whole genome sequencing was carried out on DNA samples of the proband and his parents to identify mutations associated with this disease. Sanger sequencing was performed to confirm the presence of detected variants.ResultsWhole genome sequencing revealed three missense mutations in TMBTS patient: c.1042G > A in KCNH1, c.2131 T > C in STK36, and c.726C > A in ZNF517. According to all predictors, mutation in KCNH1 is damaging de novo mutation that results in substitution of Glycine by Arginine, i.e., p.(Gly348Arg). This mutation was already reported in a patient with ZLS that could affect the connecting loop between helices S4-S5 of KCNH1 with a gain of function effect.ConclusionsOur findings demonstrate that KCNH1 mutations cause TMBTS and expand the mutational spectrum of KCNH1 in TMBTS. In addition, all cases of TMBTS were reviewed and compared to ZLS. We suggest that the two syndromes are a continuum and that the variability in the phenotypes is the result of the involvement of genetic modifiers.

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“…Patients with Keppen-Lubinsky syndrome also have microcephaly, large protruding eyes, a narrow nasal bridge, and lipodystrophy [58, 59]. Mutations in KCNH1 , a voltage gated potassium channel lead to Temple-Baraitser (also known as Zimmermann- Laband) syndrome have craniofacial defects: cleft or high arched palate, hypertelorism, dysmorphic ears, dysmorphic nose, gingival hypertrophy, an abnormal number of teeth, and limb defects such as absent or hypoplastic phalanges and nails [60–66]. Morphological defects are not limited to channelopathies that disrupt potassium channels.…”

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“…For example, such mutations in K V 7.1 cause familial atrial fibrillation, short QT syndrome, or type 2 diabetes mellitus. 26 Similarly, excessive activity of K V 10.1 underlies developmental defects that occur with seizures and cognitive impairment, such as Temple-Baraitser and Zimmermann-Laband syndromes [27][28][29][30][31] ; interestingly, excess of function of other potassium channels (SK3, K Ca 2.3) has been identified in other patients with Zimmermann-Laband syndrome. 32 In some cases, a loss of ion selectivity as a result of a mutation can be the basis for pathological phenotypes.…”

Eag1 K+ Channel: Endogenous Regulation and Functions in Nervous System

“…With the advance in the genome sequencing, the pathological functions of EAG1 channels in the nervous system are beginning to be revealed. A series of clinical observations have shown that gain-of-function of EAG1 gene mutations is strongly associated with two severe neurological and developmental disorders, Zimmermann-Laband syndrome (ZLS) [ 21 , 22 ] and Temple-Baraitser syndrome (TBS) [ 23 , 100 ]. The EAG1 mutations were also found in some undefined syndromes with intellectual disability and overlapping characters of ZLS and TBS [ 24 , 50 ], which greatly increases the appreciation about the importance of physiological function of EAG1 channels.…”

“…The EAG1 mutations were also found in some undefined syndromes with intellectual disability and overlapping characters of ZLS and TBS [ 24 , 50 ], which greatly increases the appreciation about the importance of physiological function of EAG1 channels. Here, we will review the recent literatures [ 21 – 24 , 50 , 100 ] and summarize the advances in the understanding of EAG1 channel mutations in the etiology of ZLS/TBS.…”

“…Using whole-exome sequencing (WES) technique, Simons et al [ 23 ] and Kortüm et al [ 21 ] almost simultaneously connected the genetic causes of ZLS and TBS to EAG1 channel gain-of-mutations. So far, a total of twenty-two cases with pathogenic EAG1 mutations have been reported in all six published papers [ 21 – 24 , 50 , 100 ]. Twelve different gain-of-function EAG1 mutations have been identified in twenty-two patients, in which five mutations are TBS-associated [ 23 , 100 ], six mutations are ZLS-associated [ 21 , 22 ], and four mutations are associated with atypical syndromes of ZLS/TBS as shown in Table 1 [ 24 , 50 ].…”