Temple-Baraitser Syndrome - Disorder Mechanisms

🏷

Classifications

Harrison's Chapter

Channelopathy

🔗

Mappings

MONDO

MONDO:0012735 Temple-Baraitser syndrome

Primary MONDO disease term for this entry.

👪

Inheritance

1

Autosomal dominant HP:0000006

Temple-Baraitser syndrome follows autosomal dominant inheritance with complete penetrance. The vast majority of cases arise from de novo mutations in KCNH1. Interestingly, maternal mosaicism has been documented, with some mothers carrying low-level pathogenic mutations (10-27%) and exhibiting only epilepsy without other syndromic features.

Autosomal dominant inheritance Penetrance: COMPLETE De novo rate: >90

Parent-of-origin effect: Maternal mosaicism has been reported in some cases

Show evidence (1 reference)

PMID:25420144 SUPPORT Human Clinical

"we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations."

Demonstrates that most cases are de novo but maternal mosaicism can occur with milder phenotypes.

⚙

Pathophysiology

7

KCNH1 gain-of-function mutations

Pathogenic missense mutations in KCNH1 cluster in the S4 voltage-sensor and S6 pore domains of the EAG1 (Kv10.1) voltage-gated potassium channel. These mutations produce gain-of-function effects with decreased threshold of activation and delayed deactivation, increasing channel open probability at near-resting membrane potentials.

Show evidence (2 references)

PMID:25420144 SUPPORT Human Clinical

"Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function."

Functional studies demonstrate that Temple-Baraitser syndrome mutations cause gain-of-function effects in KCNH1 channels.

PMID:26818738 SUPPORT Human Clinical

"Two novel KCNH1 mutations (p.R357Q and p.R357P), found in three patients, were located at the evolutionally highly conserved arginine in the channel voltage-sensor domain (S4). Another mutation (p.G496E) was found in the channel pore domain (S6) helix, which acts as a hinge in activation gating..."

Pathogenic variants cluster in critical S4 voltage-sensor and S6 pore domains.

Altered channel gating kinetics

Disease-associated KCNH1 variants produce leftward shifts in activation voltage-dependence, faster activation kinetics, and delayed deactivation. These biophysical changes increase channel open probability and K+ conductance at near-resting membrane potentials, altering cellular electrophysiology in both excitable and non-excitable cells.

Potassium ion transport link ↑ INCREASED Voltage-gated potassium channel activity link ↑ INCREASED

Show evidence (2 references)

PMID:41656275 SUPPORT In Vitro

"coexpression with Kv10.1 or Kv10.2 shifted the half-maximum voltage of activation in the hyperpolarizing direction"

Electrophysiology demonstrates that KCNH1 gain-of-function mutations shift activation voltage in the hyperpolarizing direction.

PMID:38372889 SUPPORT In Vitro

"ZJUCHi003-derived neurons manifested slower action potential repolarization process and wider action potential half-width than the normal neurons."

Patient-derived iPSC neurons demonstrate altered electrophysiology consistent with KCNH1 gain-of-function.

Aberrant neuronal excitability

KCNH1 gain-of-function increases K+ conductance at near-resting potentials, disrupting neuronal membrane potential dynamics, firing patterns, and network activity. The channel is predominantly expressed in glutamatergic neurons in cortical layers III and IV, where altered excitability affects both mature neuronal circuits and developing neural networks.

Neuron link Neural progenitor cell link

Regulation of neuron excitability link ↕ DYSREGULATED Synaptic transmission link ↕ DYSREGULATED

Show evidence (2 references)

PMID:27267311 SUPPORT Human Clinical

"Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood."

Clinical evidence supports a direct role of KCNH1 dysfunction in epileptogenesis through altered neuronal excitability.

PMID:41656275 SUPPORT In Vitro

"Our findings imply that interpretation of clinical symptoms related to Kv10 GoF mutations requires considering the functional crosstalk with Kv10.1 and Kv10.2 subunits, which are both expressed in glutamatergic neurons in cortical Layers III and IV."

KCNH1 gain-of-function affects glutamatergic neurons in specific cortical layers, implicating excitatory network dysfunction.

Epileptogenesis

Aberrant neuronal excitability from KCNH1 gain-of-function drives epileptiform network activity. Seizures are typically infantile-onset and include focal, generalized, and myoclonic types. EEG shows diffusely slow background with variable epileptiform abnormalities. Variant location within the channel correlates with epilepsy severity, with S4/S6 hotspot variants associated with epileptic encephalopathy.

Show evidence (2 references)

PMID:27267311 SUPPORT Human Clinical

"Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed."

High prevalence and variable seizure types documented in KCNH1-related syndromes.

PMID:36285361 SUPPORT Human Clinical

"All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1."

Genotype-phenotype correlation shows that variants in S4/S6 domains correlate with epileptic encephalopathy severity.

Impaired neurodevelopment

Altered KCNH1 channel activity during critical periods of brain development impairs neuronal differentiation, migration, and circuit formation. KCNH1 is highly expressed in the developing central nervous system, and gain-of-function effects disrupt normal developmental trajectories resulting in severe intellectual disability and global developmental delay.

Neural progenitor cell link

Nervous system development link ⚠ ABNORMAL

Show evidence (2 references)

PMID:40986435 SUPPORT Human Clinical

"these genetic disorders are now recognized as belonging to a broad spectrum of KCNH1-related encephalopathies characterized by developmental delay, intellectual disability, facial dysmorphism and infantile-onset seizures"

Review confirms that KCNH1 gain-of-function produces a spectrum of neurodevelopmental encephalopathies.

PMID:33811134 SUPPORT Human Clinical

"Affected patients have severe intellectual disability (ID) with or without epilepsy"

Severe intellectual disability is a consistent finding even in patients without classical TBS features, indicating a core neurodevelopmental mechanism.

Disrupted ciliogenesis and Hedgehog signaling

KCNH1 localizes to the base of the primary cilium in pre-ciliary vesicles and the ciliary pocket. Gain-of-function variants perturb cilia morphology, assembly/disassembly dynamics, and Sonic Hedgehog signaling. This links channel dysfunction to ectodermal and skeletal developmental defects beyond the neuronal phenotype.

Primary cilium organization link ⚠ ABNORMAL Hedgehog signaling pathway link ↕ DYSREGULATED

Show evidence (2 references)

PMID:35639255 SUPPORT In Vitro

"the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein."

Direct experimental evidence that KCNH1 gain-of-function variants disrupt primary cilia biology and Hedgehog signaling.

PMID:35639255 SUPPORT In Vitro

"KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells"

Subcellular localization of KCNH1 at the cilium base establishes a direct structural link to ciliogenesis.

Ectodermal developmental defects

Disrupted primary cilia and Hedgehog signaling pathways impair ectodermal morphogenesis, particularly affecting nail and digit development as well as craniofacial patterning. This explains the characteristic nail aplasia/hypoplasia and broadening of thumbs and great toes that are pathognomonic for Temple-Baraitser syndrome, as well as the facial dysmorphic features shared across KCNH1/KCNK4/KCNN3 channelopathies.

Show evidence (2 references)

PMID:33594261 SUPPORT Human Clinical

"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."

Shared ectodermal features across K+ channelopathies suggest a common downstream pathway affecting ectodermal development.

PMID:20683999 SUPPORT Human Clinical

"Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect."

Consistent ectodermal defects across unrelated TBS patients support a shared morphogenetic mechanism.

⬡

Causal Graph

graph LR
    Aplasia_hypoplasia_of_great_toe_nail["Aplasia/hypoplasia of great toe nail"]
    Hypotonia["Hypotonia"]
    Disrupted_ciliogenesis_and_Hedgehog_signaling["Disrupted ciliogenesis and Hedgehog signaling"]
    EEG_abnormalities["EEG abnormalities"]
    Altered_channel_gating_kinetics["Altered channel gating kinetics"]
    Ectodermal_developmental_defects["Ectodermal developmental defects"]
    KCNH1_gain_of_function_mutations["KCNH1 gain-of-function mutations"]
    Aplasia_hypoplasia_of_thumbnail["Aplasia/hypoplasia of thumbnail"]
    Wide_mouth["Wide mouth"]
    Broad_hallux["Broad hallux"]
    Aberrant_neuronal_excitability["Aberrant neuronal excitability"]
    Severe_intellectual_disability["Severe intellectual disability"]
    Global_developmental_delay["Global developmental delay"]
    Impaired_neurodevelopment["Impaired neurodevelopment"]
    Broad_thumb["Broad thumb"]
    Thick_vermilion_border["Thick vermilion border"]
    Epilepsy["Epilepsy"]
    Epileptogenesis["Epileptogenesis"]

    KCNH1_gain_of_function_mutations --> Altered_channel_gating_kinetics
    Altered_channel_gating_kinetics --> Aberrant_neuronal_excitability
    Altered_channel_gating_kinetics --> Disrupted_ciliogenesis_and_Hedgehog_signaling
    Aberrant_neuronal_excitability --> Epileptogenesis
    Aberrant_neuronal_excitability --> Impaired_neurodevelopment
    Epileptogenesis --> Epilepsy
    Epileptogenesis --> EEG_abnormalities
    Impaired_neurodevelopment --> Severe_intellectual_disability
    Impaired_neurodevelopment --> Global_developmental_delay
    Impaired_neurodevelopment --> Hypotonia
    Disrupted_ciliogenesis_and_Hedgehog_signaling --> Ectodermal_developmental_defects
    Ectodermal_developmental_defects --> Aplasia_hypoplasia_of_thumbnail
    Ectodermal_developmental_defects --> Aplasia_hypoplasia_of_great_toe_nail
    Ectodermal_developmental_defects --> Broad_thumb
    Ectodermal_developmental_defects --> Broad_hallux
    Ectodermal_developmental_defects --> Wide_mouth
    Ectodermal_developmental_defects --> Thick_vermilion_border

    style Aplasia_hypoplasia_of_great_toe_nail fill:#fef3c7
    style Hypotonia fill:#fef3c7
    style Disrupted_ciliogenesis_and_Hedgehog_signaling fill:#dbeafe
    style EEG_abnormalities fill:#fef3c7
    style Altered_channel_gating_kinetics fill:#dbeafe
    style Ectodermal_developmental_defects fill:#dbeafe
    style KCNH1_gain_of_function_mutations fill:#dbeafe
    style Aplasia_hypoplasia_of_thumbnail fill:#fef3c7
    style Wide_mouth fill:#fef3c7
    style Broad_hallux fill:#fef3c7
    style Aberrant_neuronal_excitability fill:#dbeafe
    style Severe_intellectual_disability fill:#fef3c7
    style Global_developmental_delay fill:#fef3c7
    style Impaired_neurodevelopment fill:#dbeafe
    style Broad_thumb fill:#fef3c7
    style Thick_vermilion_border fill:#fef3c7
    style Epilepsy fill:#fef3c7
    style Epileptogenesis fill:#dbeafe

●

Phenotypes

11

Head and Neck(2) Integument(2) Limbs(2) Musculoskeletal(1) Nervous System(4)

Head and Neck 2

Wide mouth FREQUENT Wide mouth (HP:0000154)

Show evidence (2 references)

PMID:26264464 SUPPORT Human Clinical

"KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes."

Clinical comparison of all published KCNH1 mutation-positive individuals identifies wide mouth as a consistent craniofacial feature.

PMID:32956079 SUPPORT Human Clinical

"mild dysmorphic facial features with a wide open mouth, a thick vermilion border of the upper lip and downturned corners of the mouth"

Case report documents wide mouth as part of TBS facial dysmorphism.

Thick vermilion border FREQUENT Thick vermilion border (HP:0012471)

Show evidence (2 references)

PMID:32956079 SUPPORT Human Clinical

"mild dysmorphic facial features with a wide open mouth, a thick vermilion border of the upper lip and downturned corners of the mouth"

Case report documents thick vermilion border as part of the characteristic TBS facial features.

PMID:25629734 SUPPORT Human Clinical

"everted and thick vermilion of both the upper and lower lips"

Clinical description of TBS patients documents thick vermilion borders as a consistent craniofacial finding.

Integument 2

Aplasia/hypoplasia of thumbnail VERY_FREQUENT Absent thumbnail (HP:0012554)

Show evidence (2 references)

PMID:20683999 SUPPORT Human Clinical

"Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect."

Clinical review of TBS patients confirms aplasia/hypoplasia of the thumbnail as a consistent finding across multiple unrelated patients.

PMID:32956079 SUPPORT Human Clinical

"nails were absent on both great toes and thumb"

Case report documenting absent thumbnail as part of the characteristic TBS presentation.

Aplasia/hypoplasia of great toe nail VERY_FREQUENT Absent nail of hallux (HP:0012555)

Show evidence (2 references)

PMID:25420144 SUPPORT Human Clinical

"Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe."

The original TBS paper identifies nail aplasia/hypoplasia of the great toe as a defining feature of the syndrome.

PMID:20683999 SUPPORT Human Clinical

"Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect."

Clinical review confirms aplasia/hypoplasia of the great toe nail as a consistent finding across TBS patients.

Limbs 2

Broad thumb VERY_FREQUENT Broad thumb (HP:0011304)

Show evidence (2 references)

PMID:26264464 SUPPORT Human Clinical

"TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails."

Clinical review identifies broad thumbs as a characteristic feature of Temple-Baraitser syndrome.

PMID:18203178 SUPPORT Human Clinical

"Our case has the additional finding of broad thumbs."

Early case report confirming broad thumbs as part of the TBS phenotype.

Broad hallux VERY_FREQUENT Broad hallux (HP:0010055)

Show evidence (2 references)

PMID:20683999 SUPPORT Human Clinical

"Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect."

Documents broadening and elongation of the halluces as a consistent pattern in TBS.

PMID:26264464 SUPPORT Human Clinical

"TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails."

Confirms broad great toes as a characteristic feature in the clinical review of KCNH1-related syndromes.

Musculoskeletal 1

Hypotonia FREQUENT Hypotonia (HP:0001252)

Show evidence (2 references)

PMID:26264464 SUPPORT Human Clinical

"KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes."

Clinical review identifies neonatal hypotonia as a common feature across KCNH1 mutation-positive individuals.

PMID:25629734 SUPPORT Human Clinical

"There was generalized hypotonia."

Clinical description of TBS patient documents generalized hypotonia as a presenting feature.

Nervous System 4

Severe intellectual disability VERY_FREQUENT Severe intellectual disability (HP:0010864)

Show evidence (2 references)

PMID:25420144 SUPPORT Human Clinical

"Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe."

The original TBS paper identifies intellectual disability as a core characteristic of the syndrome.

PMID:33811134 SUPPORT Human Clinical

"Affected patients have severe intellectual disability (ID) with or without epilepsy"

Study of seven patients with KCNH1 variants confirms severe intellectual disability as a consistent finding across the phenotypic spectrum.

Epilepsy FREQUENT Seizure (HP:0001250)

Show evidence (2 references)

PMID:27267311 SUPPORT Human Clinical

"Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed."

Systematic study of epilepsy in KCNH1-related syndromes documents the high prevalence and variable seizure types.

PMID:36285361 SUPPORT Human Clinical

"Variants in the KCNH1 cause a spectrum of epileptic disorders ranging from a benign form of genetic isolated epilepsy/FS to intractable form of epileptic encephalopathy."

Phenotypic expansion study confirms the broad spectrum of epileptic manifestations in KCNH1-related disorders.

Global developmental delay VERY_FREQUENT Global developmental delay (HP:0001263)

Show evidence (2 references)

PMID:25629734 SUPPORT Human Clinical

"This study reports on two individuals with Temple-Baraitser syndrome, manifesting typical hallux and pollex findings, global developmental delay, and seizures."

Clinical study identifies global developmental delay as a consistent feature of TBS.

PMID:40986435 SUPPORT Human Clinical

"these genetic disorders are now recognized as belonging to a broad spectrum of KCNH1-related encephalopathies characterized by developmental delay, intellectual disability, facial dysmorphism and infantile-onset seizures"

Recent review confirms developmental delay as a core feature of KCNH1-related disorders.

EEG abnormalities VERY_FREQUENT EEG abnormality (HP:0002353)

Show evidence (2 references)

PMID:27267311 SUPPORT Human Clinical

"EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities."

Systematic study of epilepsy in KCNH1-related syndromes documents EEG abnormalities as a universal finding in affected individuals with epilepsy.

PMID:32956079 SUPPORT Human Clinical

"Electroencephalogram showed a diffusely slow background."

Case report confirms diffusely slow EEG background as a characteristic finding in TBS.

🧬

Genetic Associations

1

KCNH1 pathogenic variants (Causative)

Show evidence (1 reference)

PMID:25420144 SUPPORT Human Clinical

"Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS."

Establishes KCNH1 mutations as the genetic cause of Temple-Baraitser syndrome.

💊

Treatments

4

Antiepileptic drugs MAXO:0000058

Drug: topiramate ↗ carbamazepine ↗

Standard antiepileptic medications are used to manage seizures in affected individuals, though specific drug efficacy may vary based on seizure type and individual response. Given the gain-of-function mechanism, channel blockade represents a rational therapeutic strategy, though precision anti-seizure efficacy for KCNH1 gain-of-function remains investigational.

Target Phenotypes: Epilepsy ↗ EEG abnormality ↗

Show evidence (2 references)

PMID:27267311 SUPPORT Human Clinical

"Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients."

Systematic study documents the variable response to antiepileptic drug therapy in KCNH1-related epilepsy.

PMID:40986435 SUPPORT Human Clinical

"We argue that allosteric modulators of Kv10.1 that induce a depolarizing shift in the channel's activation threshold are more likely to provide seizure control in KCNH1 epilepsy patients than pore blockers that annihilate channel function."

Recent review supports the theoretical basis for targeted channel modulation as a rational therapeutic strategy.

Supportive developmental therapies MAXO:0000011

Comprehensive developmental support including physical therapy, occupational therapy, and speech therapy to maximize developmental potential despite severe intellectual disability.

Target Phenotypes: Global developmental delay ↗ Severe intellectual disability ↗ Hypotonia ↗

Show evidence (2 references)

PMID:40604848 SUPPORT Human Clinical

"The first step of oral treatment consisted of myofunctional and speech/language therapy to stimulate biting and chewing. It also helped with the rehabilitation of proper tongue function."

Case report documents the use of myofunctional and speech/language therapy as part of a comprehensive treatment protocol for KCNH1-related syndrome.

PMID:25629734 SUPPORT Human Clinical

"By 5 years of age she started using single words and was able to feed herself using utensils."

Natural history documentation shows that TBS patients can achieve developmental milestones over time, supporting the role of ongoing developmental therapies.

Special education and behavioral support MAXO:0000950

Specialized educational interventions and behavioral support tailored to the severe intellectual disability and developmental needs of affected individuals.

Target Phenotypes: Severe intellectual disability ↗ Global developmental delay ↗

Show evidence (2 references)

PMID:25629734 SUPPORT Human Clinical

"At 9.5 years of age she had a vocabulary of ~40 words, followed a one-step command, walked up and down stairs, and rode a three-wheeled toy."

Detailed functional assessment of a TBS patient documents capacity for learning and skill acquisition over time, supporting the need for tailored educational interventions.

PMID:37817707 SUPPORT Human Clinical

"caused pharma coresistantseizures and autistic behaviour in a 2.7-year-old boy"

Report of autistic behavior in a patient with KCNH1 mutation highlights the need for behavioral support alongside educational interventions.

Genetic counseling MAXO:0000079

Comprehensive genetic counseling is important for families given the autosomal dominant inheritance pattern, high de novo mutation rate, and documented cases of maternal mosaicism with variable penetrance.

Show evidence (2 references)

PMID:25420144 SUPPORT Human Clinical

"we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations."

Discovery of maternal mosaicism with variable phenotypic expression highlights the critical importance of genetic counseling for recurrence risk assessment and parental testing.

PMID:36285361 SUPPORT Human Clinical

"All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1."

Genotype-phenotype correlations based on variant location provide important information for prognostic counseling of affected families.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Temple-Baraitser Syndrome:

Zimmermann-Laband syndrome Not Yet Curated MONDO:0000200

Overlapping Features The most important differential for Temple-Baraitser syndrome. Both are caused by gain-of-function mutations in KCNH1 and share intellectual disability, nail hypoplasia/aplasia, and facial dysmorphism. Some authors consider them a continuum rather than distinct entities.

Distinguishing Features

ZLS features prominent gingival fibromatosis/enlargement, which is less common in TBS
ZLS shows coarsening of the face and a characteristically large nose
Hypertrichosis is more prominent in ZLS
Epilepsy is more consistently associated with TBS than ZLS
Nail hypoplasia of thumbs and great toes may be milder in ZLS

Show evidence (2 references)

PMID:26264464 SUPPORT Human Clinical

"ZLS is characterized by facial dysmorphism including coarsening of the face and a large nose, gingival enlargement, ID, hypoplasia of terminal phalanges and nails and hypertrichosis."

Clinical comparison of KCNH1 mutation-positive individuals highlights the phenotypic overlap and distinguishing features between TBS and ZLS.

PMID:27282200 SUPPORT Human Clinical

"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."

Analysis of shared KCNH1 mutations between TBS and ZLS patients supports a phenotypic continuum rather than distinct entities.

FHEIG syndrome Not Yet Curated MONDO:0032714

Overlapping Features Caused by gain-of-function variants in KCNK4, another potassium channel gene. Shares facial dysmorphism, hypertrichosis, epilepsy, intellectual disability, and gingival overgrowth with TBS/ZLS, reflecting a common downstream effect of increased K+ conductance on ectodermal and neural development.

Distinguishing Features

FHEIG is caused by KCNK4 variants rather than KCNH1
Nail aplasia/hypoplasia of thumbs and great toes is more prominent in TBS
Broadening and elongation of thumbs and halluces is pathognomonic for TBS

Show evidence (2 references)

PMID:33594261 SUPPORT Human Clinical

"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."

Systematic comparison identifies shared features across K+ channelopathies, defining a subgroup of syndromic neurodevelopmental K+ channelopathies.

PMID:32560786 SUPPORT Human Clinical

"Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome."

Review groups TBS and FHEIG together as related dysmorphic potassium channelopathies.

KCNN3-related neurodevelopmental disorder

Overlapping Features Caused by gain-of-function variants in KCNN3, encoding a calcium-activated potassium channel. Shares coarse facial features, gingival enlargement, digital hypoplasia, and intellectual disability with TBS.

Distinguishing Features

Caused by KCNN3 variants rather than KCNH1
The specific pattern of nail aplasia/hypoplasia and broadened first rays typical of TBS is not observed
KCNN3 encodes a calcium-activated rather than voltage-gated K+ channel

Show evidence (1 reference)

PMID:33594261 SUPPORT Human Clinical

"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."

Clinical review proposes grouping KCNH1, KCNK4, and KCNN3-related disorders as a subclass of K+ channelopathies with overlapping features.

KCNH1-related intellectual disability without syndromic features

Overlapping Features Some patients with pathogenic KCNH1 variants present with severe intellectual disability and epilepsy but lack the characteristic nail and digit anomalies of classical TBS or the gingival fibromatosis of ZLS, representing the mildest end of the KCNH1 phenotypic spectrum.

Distinguishing Features

Absence of nail aplasia/hypoplasia of thumbs and great toes
Absence of broadened thumbs and halluces
Absence of gingival fibromatosis
Facial dysmorphism may be subtle or nonspecific

Show evidence (2 references)

PMID:33811134 SUPPORT Human Clinical

"Affected patients have severe intellectual disability (ID) with or without epilepsy"

Study of seven patients with KCNH1 variants who lack distinctive TBS/ZLS features expands the phenotypic spectrum.

PMID:26264464 SUPPORT Human Clinical

"Neither TMBTS nor ZLS was suspected clinically."

Some patients with KCNH1 mutations were not clinically suspected of TBS or ZLS, demonstrating that nail/digit features can be mild or absent.

🔬

Clinical Trials

3

NCT06380192 NOT_APPLICABLE RECRUITING

A French national retrospective natural history study collecting clinical data on patients with developmental and epileptic encephalopathy (DEE) of genetic etiology. By building a large-scale database of DEE patients stratified by genetic cause, this study aims to identify biomarkers, improve classification, and develop personalized management recommendations. KCNH1-related DEE patients would be eligible for inclusion.

Target Phenotypes: Epilepsy ↗ Global developmental delay ↗ Severe intellectual disability ↗

Show evidence (1 reference)

clinicaltrials:NCT06380192 SUPPORT

"The creation of a database with retrospective follow-up of a large number of patients on a national scale will enable better knowledge of specific biomarkers, and thus a better classification and understanding of the natural evolution of DEE according to their etiology."

Natural history study for genetically-caused DEE could include KCNH1/Temple-Baraitser patients, providing data on disease progression and biomarkers for this ultra-rare condition.

NCT06700811 PHASE_I RECRUITING

A single-center pilot study evaluating the safety and feasibility of early ketogenic diet administration to prevent epileptic spasms in infants with genetic seizure disorders. Ketogenic diet is an established non-medication treatment for difficult-to-control seizures. Infants with KCNH1-related genetic epilepsy could qualify for this preventive intervention approach.

Target Phenotypes: Epilepsy ↗

Show evidence (1 reference)

clinicaltrials:NCT06700811 SUPPORT

"Epileptic spasms (ES) are a predominantly infantile seizure type observed frequently in certain genetic disorders. Ketogenic diet (high ratio of fat to carbohydrate/protein) is an established non-medication treatment for difficult to control seizures, including ES."

Pilot trial of ketogenic diet for prevention of epileptic spasms in genetic epilepsies is relevant to the infantile-onset seizures characteristic of Temple-Baraitser syndrome.

NCT06278428 NOT_APPLICABLE RECRUITING

An observational study examining the genotype-phenotype correlations and disease progression of developmental epileptic encephalopathy with onset before 2 years of age. The study follows patients for 2 years to characterize the natural history of genetically-caused DEE, which is directly relevant to understanding the early course of KCNH1-related encephalopathy.

Target Phenotypes: Epilepsy ↗ Severe intellectual disability ↗ Global developmental delay ↗

Show evidence (1 reference)

clinicaltrials:NCT06278428 SUPPORT

"Children with epileptic and developmental encephalopathy due to genetic causes are at higher risk of developing neurodevelopmental disorders than children with epileptic and developmental encephalopathy due to other causes."

Study of genotype-phenotype correlations in early-onset DEE is relevant to understanding disease progression in KCNH1-related encephalopathy, where seizures typically begin in infancy.

{ }

Source YAML

click to show

name: Temple-Baraitser Syndrome
creation_date: '2026-02-14T20:42:23Z'
updated_date: '2026-02-15T16:14:47Z'
category: Mendelian
description: >
  Temple-Baraitser syndrome is a rare autosomal dominant neurodevelopmental disorder
  caused by gain-of-function mutations in KCNH1, which encodes the EAG1 voltage-gated
  potassium channel. The syndrome is characterized by severe intellectual disability,
  epilepsy, and distinctive limb anomalies including hypoplasia or aplasia of the
  thumbnails and great-toe nails with broadening and elongation of the thumbs and
  halluces. Additional features include characteristic facial dysmorphism with wide
  mouth and thick vermilion borders, developmental delays, and variable craniofacial
  abnormalities. Most cases arise from de novo mutations, though maternal mosaicism
  has been reported. The condition represents part of a spectrum that may overlap
  with Zimmermann-Laband syndrome.
synonyms:
- TBS
- TMBTS
- Temple-Baraitser syndrome
- KCNH1-related neurodevelopmental disorder
- EAG1-related syndrome
disease_term:
  preferred_term: Temple-Baraitser syndrome
  term:
    id: MONDO:0012735
    label: Temple-Baraitser syndrome
parents:
- Neurodevelopmental disorder
- Channelopathy
- Intellectual disability syndrome
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  de_novo_rate: ">90"
  parent_of_origin_effect: Maternal mosaicism has been reported in some cases
  description: >
    Temple-Baraitser syndrome follows autosomal dominant inheritance with complete
    penetrance. The vast majority of cases arise from de novo mutations in KCNH1.
    Interestingly, maternal mosaicism has been documented, with some mothers carrying
    low-level pathogenic mutations (10-27%) and exhibiting only epilepsy without
    other syndromic features.
  evidence:
  - reference: PMID:25420144
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations."
    explanation: Demonstrates that most cases are de novo but maternal mosaicism can occur with milder phenotypes.
pathophysiology:
- name: KCNH1 gain-of-function mutations
  description: >
    Pathogenic missense mutations in KCNH1 cluster in the S4 voltage-sensor
    and S6 pore domains of the EAG1 (Kv10.1) voltage-gated potassium channel.
    These mutations produce gain-of-function effects with decreased threshold
    of activation and delayed deactivation, increasing channel open probability
    at near-resting membrane potentials.
  gene:
    preferred_term: KCNH1
    description: Voltage-gated potassium channel gene encoding EAG1 (ether à go-go 1) channel, predominantly expressed in the central nervous system.
    modifier: INCREASED
    term:
      id: hgnc:6251
      label: KCNH1
  evidence:
  - reference: PMID:25420144
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function."
    explanation: Functional studies demonstrate that Temple-Baraitser syndrome mutations cause gain-of-function effects in KCNH1 channels.
  - reference: PMID:26818738
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two novel KCNH1 mutations (p.R357Q and p.R357P), found in three patients, were located at the evolutionally highly conserved arginine in the channel voltage-sensor domain (S4). Another mutation (p.G496E) was found in the channel pore domain (S6) helix, which acts as a hinge in activation gating and mainly conducts non-inactivating outward potassium current."
    explanation: Pathogenic variants cluster in critical S4 voltage-sensor and S6 pore domains.
  downstream:
  - target: Altered channel gating kinetics
    description: Mutations shift activation threshold and delay deactivation, increasing K+ conductance at near-resting potentials.
- name: Altered channel gating kinetics
  description: >
    Disease-associated KCNH1 variants produce leftward shifts in activation
    voltage-dependence, faster activation kinetics, and delayed deactivation.
    These biophysical changes increase channel open probability and K+
    conductance at near-resting membrane potentials, altering cellular
    electrophysiology in both excitable and non-excitable cells.
  biological_processes:
  - preferred_term: Potassium ion transport
    modifier: INCREASED
    term:
      id: GO:0006813
      label: potassium ion transport
  - preferred_term: Voltage-gated potassium channel activity
    modifier: INCREASED
    term:
      id: GO:0005249
      label: voltage-gated potassium channel activity
  evidence:
  - reference: PMID:41656275
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "coexpression with Kv10.1 or Kv10.2 shifted the half-maximum voltage of activation in the hyperpolarizing direction"
    explanation: Electrophysiology demonstrates that KCNH1 gain-of-function mutations shift activation voltage in the hyperpolarizing direction.
  - reference: PMID:38372889
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ZJUCHi003-derived neurons manifested slower action potential repolarization process and wider action potential half-width than the normal neurons."
    explanation: Patient-derived iPSC neurons demonstrate altered electrophysiology consistent with KCNH1 gain-of-function.
  downstream:
  - target: Aberrant neuronal excitability
    description: Altered K+ channel kinetics disrupt neuronal membrane potential dynamics and firing patterns.
  - target: Disrupted ciliogenesis and Hedgehog signaling
    description: Hyperactive KCNH1 at the ciliary base perturbs primary cilium biology in non-excitable cells.
- name: Aberrant neuronal excitability
  description: >
    KCNH1 gain-of-function increases K+ conductance at near-resting potentials,
    disrupting neuronal membrane potential dynamics, firing patterns, and network
    activity. The channel is predominantly expressed in glutamatergic neurons
    in cortical layers III and IV, where altered excitability affects both
    mature neuronal circuits and developing neural networks.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: Neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: Regulation of neuron excitability
    modifier: DYSREGULATED
    term:
      id: GO:0050805
      label: regulation of neuron excitability
  - preferred_term: Synaptic transmission
    modifier: DYSREGULATED
    term:
      id: GO:0007268
      label: synaptic transmission
  evidence:
  - reference: PMID:27267311
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood."
    explanation: Clinical evidence supports a direct role of KCNH1 dysfunction in epileptogenesis through altered neuronal excitability.
  - reference: PMID:41656275
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings imply that interpretation of clinical symptoms related to Kv10 GoF mutations requires considering the functional crosstalk with Kv10.1 and Kv10.2 subunits, which are both expressed in glutamatergic neurons in cortical Layers III and IV."
    explanation: KCNH1 gain-of-function affects glutamatergic neurons in specific cortical layers, implicating excitatory network dysfunction.
  downstream:
  - target: Epileptogenesis
    description: Hyperexcitable neuronal networks produce abnormal synchronous discharges and epileptiform activity.
  - target: Impaired neurodevelopment
    description: Altered neuronal excitability during critical developmental periods disrupts brain maturation.
- name: Epileptogenesis
  description: >
    Aberrant neuronal excitability from KCNH1 gain-of-function drives
    epileptiform network activity. Seizures are typically infantile-onset
    and include focal, generalized, and myoclonic types. EEG shows diffusely
    slow background with variable epileptiform abnormalities. Variant location
    within the channel correlates with epilepsy severity, with S4/S6 hotspot
    variants associated with epileptic encephalopathy.
  evidence:
  - reference: PMID:27267311
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed."
    explanation: High prevalence and variable seizure types documented in KCNH1-related syndromes.
  - reference: PMID:36285361
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1."
    explanation: Genotype-phenotype correlation shows that variants in S4/S6 domains correlate with epileptic encephalopathy severity.
  downstream:
  - target: Epilepsy
    description: Recurrent seizures from hyperexcitable neuronal networks.
  - target: EEG abnormalities
    description: Diffusely slow background and multifocal epileptiform discharges.
- name: Impaired neurodevelopment
  description: >
    Altered KCNH1 channel activity during critical periods of brain development
    impairs neuronal differentiation, migration, and circuit formation.
    KCNH1 is highly expressed in the developing central nervous system,
    and gain-of-function effects disrupt normal developmental trajectories
    resulting in severe intellectual disability and global developmental delay.
  cell_types:
  - preferred_term: Neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: Nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0007399
      label: nervous system development
  evidence:
  - reference: PMID:40986435
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these genetic disorders are now recognized as belonging to a broad spectrum of KCNH1-related encephalopathies characterized by developmental delay, intellectual disability, facial dysmorphism and infantile-onset seizures"
    explanation: Review confirms that KCNH1 gain-of-function produces a spectrum of neurodevelopmental encephalopathies.
  - reference: PMID:33811134
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients have severe intellectual disability (ID) with or without epilepsy"
    explanation: Severe intellectual disability is a consistent finding even in patients without classical TBS features, indicating a core neurodevelopmental mechanism.
  downstream:
  - target: Severe intellectual disability
    description: Disrupted brain development results in severe cognitive impairment.
  - target: Global developmental delay
    description: Impaired neuronal maturation causes delays across motor, speech, and cognitive domains.
  - target: Hypotonia
    description: Aberrant neurodevelopment contributes to decreased muscle tone.
- name: Disrupted ciliogenesis and Hedgehog signaling
  description: >
    KCNH1 localizes to the base of the primary cilium in pre-ciliary vesicles
    and the ciliary pocket. Gain-of-function variants perturb cilia morphology,
    assembly/disassembly dynamics, and Sonic Hedgehog signaling. This links
    channel dysfunction to ectodermal and skeletal developmental defects
    beyond the neuronal phenotype.
  biological_processes:
  - preferred_term: Primary cilium organization
    modifier: ABNORMAL
    term:
      id: GO:0035994
      label: primary cilium organization
  - preferred_term: Hedgehog signaling pathway
    modifier: DYSREGULATED
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  evidence:
  - reference: PMID:35639255
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein."
    explanation: Direct experimental evidence that KCNH1 gain-of-function variants disrupt primary cilia biology and Hedgehog signaling.
  - reference: PMID:35639255
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells"
    explanation: Subcellular localization of KCNH1 at the cilium base establishes a direct structural link to ciliogenesis.
  downstream:
  - target: Ectodermal developmental defects
    description: Disrupted Hedgehog signaling impairs ectodermal morphogenesis including nail and digit development.
- name: Ectodermal developmental defects
  description: >
    Disrupted primary cilia and Hedgehog signaling pathways impair ectodermal
    morphogenesis, particularly affecting nail and digit development as well
    as craniofacial patterning. This explains the characteristic nail
    aplasia/hypoplasia and broadening of thumbs and great toes that are
    pathognomonic for Temple-Baraitser syndrome, as well as the facial
    dysmorphic features shared across KCNH1/KCNK4/KCNN3 channelopathies.
  evidence:
  - reference: PMID:33594261
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Shared ectodermal features across K+ channelopathies suggest a common downstream pathway affecting ectodermal development.
  - reference: PMID:20683999
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect."
    explanation: Consistent ectodermal defects across unrelated TBS patients support a shared morphogenetic mechanism.
  downstream:
  - target: Aplasia/hypoplasia of thumbnail
    description: Disrupted nail morphogenesis in the first ray of the hand.
  - target: Aplasia/hypoplasia of great toe nail
    description: Disrupted nail morphogenesis in the first ray of the foot.
  - target: Broad thumb
    description: Abnormal digit morphogenesis produces broadened and elongated thumbs.
  - target: Broad hallux
    description: Abnormal digit morphogenesis produces broadened and elongated great toes.
  - target: Wide mouth
    description: Disrupted craniofacial patterning affects oral aperture development.
  - target: Thick vermilion border
    description: Abnormal craniofacial morphogenesis produces thickened lip borders.
phenotypes:
- name: Severe intellectual disability
  description: >
    Affected individuals typically have severe global developmental delay with
    little to no speech development. Intellectual disability is a consistent
    and prominent feature of the syndrome.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: PMID:25420144
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe."
    explanation: The original TBS paper identifies intellectual disability as a core characteristic of the syndrome.
  - reference: PMID:33811134
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients have severe intellectual disability (ID) with or without epilepsy"
    explanation: Study of seven patients with KCNH1 variants confirms severe intellectual disability as a consistent finding across the phenotypic spectrum.
- name: Epilepsy
  description: >
    Seizures are a common feature of Temple-Baraitser syndrome, often beginning
    in early childhood. The epilepsy can be variable in type and severity,
    including focal, generalized, and myoclonic seizures with multifocal
    epileptiform EEG abnormalities.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27267311
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed."
    explanation: Systematic study of epilepsy in KCNH1-related syndromes documents the high prevalence and variable seizure types.
  - reference: PMID:36285361
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in the KCNH1 cause a spectrum of epileptic disorders ranging from a benign form of genetic isolated epilepsy/FS to intractable form of epileptic encephalopathy."
    explanation: Phenotypic expansion study confirms the broad spectrum of epileptic manifestations in KCNH1-related disorders.
- name: Aplasia/hypoplasia of thumbnail
  description: >
    Characteristic absence or severe underdevelopment of the thumbnail is a
    diagnostic hallmark of Temple-Baraitser syndrome.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Absent thumbnail
    term:
      id: HP:0012554
      label: Absent thumbnail
  evidence:
  - reference: PMID:20683999
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect."
    explanation: Clinical review of TBS patients confirms aplasia/hypoplasia of the thumbnail as a consistent finding across multiple unrelated patients.
  - reference: PMID:32956079
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nails were absent on both great toes and thumb"
    explanation: Case report documenting absent thumbnail as part of the characteristic TBS presentation.
- name: Aplasia/hypoplasia of great toe nail
  description: >
    Absence or severe underdevelopment of the great toe nail, often
    accompanied by broadening and elongation of the great toe.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Absent nail of hallux
    term:
      id: HP:0012555
      label: Absent nail of hallux
  evidence:
  - reference: PMID:25420144
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe."
    explanation: The original TBS paper identifies nail aplasia/hypoplasia of the great toe as a defining feature of the syndrome.
  - reference: PMID:20683999
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect."
    explanation: Clinical review confirms aplasia/hypoplasia of the great toe nail as a consistent finding across TBS patients.
- name: Broad thumb
  description: >
    The thumbs typically appear broadened and elongated with a tubular
    appearance, often accompanying the nail aplasia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Broad thumb
    term:
      id: HP:0011304
      label: Broad thumb
  evidence:
  - reference: PMID:26264464
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails."
    explanation: Clinical review identifies broad thumbs as a characteristic feature of Temple-Baraitser syndrome.
  - reference: PMID:18203178
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our case has the additional finding of broad thumbs."
    explanation: Early case report confirming broad thumbs as part of the TBS phenotype.
- name: Broad hallux
  description: >
    The great toes show broadening, elongation, and tubular appearance
    similar to the thumbs.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
  evidence:
  - reference: PMID:20683999
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect."
    explanation: Documents broadening and elongation of the halluces as a consistent pattern in TBS.
  - reference: PMID:26264464
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails."
    explanation: Confirms broad great toes as a characteristic feature in the clinical review of KCNH1-related syndromes.
- name: Wide mouth
  description: >
    Characteristic facial feature with an abnormally wide oral aperture,
    contributing to the distinctive facial dysmorphism.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:26264464
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes."
    explanation: Clinical comparison of all published KCNH1 mutation-positive individuals identifies wide mouth as a consistent craniofacial feature.
  - reference: PMID:32956079
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild dysmorphic facial features with a wide open mouth, a thick vermilion border of the upper lip and downturned corners of the mouth"
    explanation: Case report documents wide mouth as part of TBS facial dysmorphism.
- name: Thick vermilion border
  description: >
    Prominent, thickened borders of the lips, particularly affecting the
    upper lip as part of the facial dysmorphism.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thick vermilion border
    term:
      id: HP:0012471
      label: Thick vermilion border
  evidence:
  - reference: PMID:32956079
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild dysmorphic facial features with a wide open mouth, a thick vermilion border of the upper lip and downturned corners of the mouth"
    explanation: Case report documents thick vermilion border as part of the characteristic TBS facial features.
  - reference: PMID:25629734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "everted and thick vermilion of both the upper and lower lips"
    explanation: Clinical description of TBS patients documents thick vermilion borders as a consistent craniofacial finding.
- name: Global developmental delay
  description: >
    Significant delays across multiple developmental domains including motor,
    speech, cognitive, and social development.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:25629734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study reports on two individuals with Temple-Baraitser syndrome, manifesting typical hallux and pollex findings, global developmental delay, and seizures."
    explanation: Clinical study identifies global developmental delay as a consistent feature of TBS.
  - reference: PMID:40986435
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these genetic disorders are now recognized as belonging to a broad spectrum of KCNH1-related encephalopathies characterized by developmental delay, intellectual disability, facial dysmorphism and infantile-onset seizures"
    explanation: Recent review confirms developmental delay as a core feature of KCNH1-related disorders.
- name: Hypotonia
  description: >
    Decreased muscle tone is commonly observed in Temple-Baraitser syndrome,
    contributing to motor developmental delays and feeding difficulties.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:26264464
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes."
    explanation: Clinical review identifies neonatal hypotonia as a common feature across KCNH1 mutation-positive individuals.
  - reference: PMID:25629734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was generalized hypotonia."
    explanation: Clinical description of TBS patient documents generalized hypotonia as a presenting feature.
- name: EEG abnormalities
  description: >
    Electroencephalographic abnormalities including multifocal spikes and sharp
    waves, epileptiform patterns, and abnormal background activity are characteristic
    findings supporting the underlying channelopathy.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:27267311
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities."
    explanation: Systematic study of epilepsy in KCNH1-related syndromes documents EEG abnormalities as a universal finding in affected individuals with epilepsy.
  - reference: PMID:32956079
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electroencephalogram showed a diffusely slow background."
    explanation: Case report confirms diffusely slow EEG background as a characteristic finding in TBS.
genetic:
- name: KCNH1 pathogenic variants
  association: Causative
  notes: >
    Temple-Baraitser syndrome is caused by heterozygous pathogenic variants
    in KCNH1 that result in gain-of-function effects. Multiple missense
    mutations have been identified at highly conserved residues. The mutations
    typically occur de novo, though maternal mosaicism has been reported.
  evidence:
  - reference: PMID:25420144
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS."
    explanation: Establishes KCNH1 mutations as the genetic cause of Temple-Baraitser syndrome.
  variants:
  - name: Heterozygous missense mutations
    description: Various missense mutations at highly conserved residues causing gain-of-function effects.
    evidence:
    - reference: PMID:32956079
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole genome sequencing identified one pathogenic missense mutation in KCNH1 (c. 1529 A > C; Asn510Thr) in this TMBTS patient."
      explanation: Clinical case report demonstrating identification of a pathogenic KCNH1 missense mutation in Temple-Baraitser syndrome.
    - reference: PMID:26818738
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two novel KCNH1 mutations (p.R357Q and p.R357P), found in three patients, were located at the evolutionally highly conserved arginine in the channel voltage-sensor domain (S4). Another mutation (p.G496E) was found in the channel pore domain (S6) helix, which acts as a hinge in activation gating and mainly conducts non-inactivating outward potassium current."
      explanation: Molecular diagnostics reveal that pathogenic variants cluster in critical S4 and S6 channel domains responsible for voltage sensing and gating.
    - reference: PMID:36285361
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1."
      explanation: Genotype-phenotype correlation study demonstrates that variant location within the channel determines clinical severity.
treatments:
- name: Antiepileptic drugs
  description: >
    Standard antiepileptic medications are used to manage seizures in affected
    individuals, though specific drug efficacy may vary based on seizure type
    and individual response. Given the gain-of-function mechanism, channel
    blockade represents a rational therapeutic strategy, though precision
    anti-seizure efficacy for KCNH1 gain-of-function remains investigational.
  treatment_term:
    preferred_term: Antiepileptic drug therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
  target_phenotypes:
  - preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:27267311
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients."
    explanation: Systematic study documents the variable response to antiepileptic drug therapy in KCNH1-related epilepsy.
  - reference: PMID:40986435
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We argue that allosteric modulators of Kv10.1 that induce a depolarizing shift in the channel's activation threshold are more likely to provide seizure control in KCNH1 epilepsy patients than pore blockers that annihilate channel function."
    explanation: Recent review supports the theoretical basis for targeted channel modulation as a rational therapeutic strategy.
- name: Supportive developmental therapies
  description: >
    Comprehensive developmental support including physical therapy, occupational
    therapy, and speech therapy to maximize developmental potential despite
    severe intellectual disability.
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40604848
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first step of oral treatment consisted of myofunctional and speech/language therapy to stimulate biting and chewing. It also helped with the rehabilitation of proper tongue function."
    explanation: Case report documents the use of myofunctional and speech/language therapy as part of a comprehensive treatment protocol for KCNH1-related syndrome.
  - reference: PMID:25629734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By 5 years of age she started using single words and was able to feed herself using utensils."
    explanation: Natural history documentation shows that TBS patients can achieve developmental milestones over time, supporting the role of ongoing developmental therapies.
- name: Special education and behavioral support
  description: >
    Specialized educational interventions and behavioral support tailored
    to the severe intellectual disability and developmental needs of affected
    individuals.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:25629734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 9.5 years of age she had a vocabulary of ~40 words, followed a one-step command, walked up and down stairs, and rode a three-wheeled toy."
    explanation: Detailed functional assessment of a TBS patient documents capacity for learning and skill acquisition over time, supporting the need for tailored educational interventions.
  - reference: PMID:37817707
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "caused pharma coresistantseizures and autistic behaviour in a 2.7-year-old boy"
    explanation: Report of autistic behavior in a patient with KCNH1 mutation highlights the need for behavioral support alongside educational interventions.
- name: Genetic counseling
  description: >
    Comprehensive genetic counseling is important for families given the
    autosomal dominant inheritance pattern, high de novo mutation rate,
    and documented cases of maternal mosaicism with variable penetrance.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:25420144
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations."
    explanation: Discovery of maternal mosaicism with variable phenotypic expression highlights the critical importance of genetic counseling for recurrence risk assessment and parental testing.
  - reference: PMID:36285361
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1."
    explanation: Genotype-phenotype correlations based on variant location provide important information for prognostic counseling of affected families.
differential_diagnoses:
- name: Zimmermann-Laband syndrome
  description: >
    The most important differential for Temple-Baraitser syndrome. Both are caused
    by gain-of-function mutations in KCNH1 and share intellectual disability, nail
    hypoplasia/aplasia, and facial dysmorphism. Some authors consider them a
    continuum rather than distinct entities.
  disease_term:
    preferred_term: Zimmermann-Laband syndrome
    term:
      id: MONDO:0000200
      label: Zimmermann-Laband syndrome
  distinguishing_features:
  - ZLS features prominent gingival fibromatosis/enlargement, which is less common in TBS
  - ZLS shows coarsening of the face and a characteristically large nose
  - Hypertrichosis is more prominent in ZLS
  - Epilepsy is more consistently associated with TBS than ZLS
  - Nail hypoplasia of thumbs and great toes may be milder in ZLS
  evidence:
  - reference: PMID:26264464
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ZLS is characterized by facial dysmorphism including coarsening of the face and a large nose, gingival enlargement, ID, hypoplasia of terminal phalanges and nails and hypertrichosis."
    explanation: Clinical comparison of KCNH1 mutation-positive individuals highlights the phenotypic overlap and distinguishing features between TBS and ZLS.
  - reference: PMID:27282200
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Analysis of shared KCNH1 mutations between TBS and ZLS patients supports a phenotypic continuum rather than distinct entities.
- name: FHEIG syndrome
  description: >
    Caused by gain-of-function variants in KCNK4, another potassium channel gene.
    Shares facial dysmorphism, hypertrichosis, epilepsy, intellectual disability,
    and gingival overgrowth with TBS/ZLS, reflecting a common downstream effect
    of increased K+ conductance on ectodermal and neural development.
  disease_term:
    preferred_term: FHEIG syndrome
    term:
      id: MONDO:0032714
      label: facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome
  distinguishing_features:
  - FHEIG is caused by KCNK4 variants rather than KCNH1
  - Nail aplasia/hypoplasia of thumbs and great toes is more prominent in TBS
  - Broadening and elongation of thumbs and halluces is pathognomonic for TBS
  evidence:
  - reference: PMID:33594261
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Systematic comparison identifies shared features across K+ channelopathies, defining a subgroup of syndromic neurodevelopmental K+ channelopathies.
  - reference: PMID:32560786
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome."
    explanation: Review groups TBS and FHEIG together as related dysmorphic potassium channelopathies.
- name: KCNN3-related neurodevelopmental disorder
  description: >
    Caused by gain-of-function variants in KCNN3, encoding a calcium-activated
    potassium channel. Shares coarse facial features, gingival enlargement,
    digital hypoplasia, and intellectual disability with TBS.
  distinguishing_features:
  - Caused by KCNN3 variants rather than KCNH1
  - The specific pattern of nail aplasia/hypoplasia and broadened first rays typical of TBS is not observed
  - KCNN3 encodes a calcium-activated rather than voltage-gated K+ channel
  evidence:
  - reference: PMID:33594261
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Clinical review proposes grouping KCNH1, KCNK4, and KCNN3-related disorders as a subclass of K+ channelopathies with overlapping features.
- name: KCNH1-related intellectual disability without syndromic features
  description: >
    Some patients with pathogenic KCNH1 variants present with severe intellectual
    disability and epilepsy but lack the characteristic nail and digit anomalies
    of classical TBS or the gingival fibromatosis of ZLS, representing the mildest
    end of the KCNH1 phenotypic spectrum.
  distinguishing_features:
  - Absence of nail aplasia/hypoplasia of thumbs and great toes
  - Absence of broadened thumbs and halluces
  - Absence of gingival fibromatosis
  - Facial dysmorphism may be subtle or nonspecific
  evidence:
  - reference: PMID:33811134
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients have severe intellectual disability (ID) with or without epilepsy"
    explanation: Study of seven patients with KCNH1 variants who lack distinctive TBS/ZLS features expands the phenotypic spectrum.
  - reference: PMID:26264464
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neither TMBTS nor ZLS was suspected clinically."
    explanation: Some patients with KCNH1 mutations were not clinically suspected of TBS or ZLS, demonstrating that nail/digit features can be mild or absent.
notes: >
  Temple-Baraitser syndrome is notable for its distinctive combination of severe
  intellectual disability, epilepsy, and characteristic limb anomalies affecting
  the first rays. The nail aplasia/hypoplasia of thumbs and great toes with
  associated broadening is pathognomonic. The syndrome has clinical and genetic
  overlap with Zimmermann-Laband syndrome, suggesting these may represent a
  continuum of KCNH1-related disorders. The gain-of-function mechanism in a
  voltage-gated potassium channel represents an important example of how
  channelopathies can cause complex neurodevelopmental phenotypes. Recent
  molecular studies reveal that pathogenic variants cluster in critical S4-S6
  domains (exons 7-8) responsible for voltage sensing and channel gating,
  producing characteristic biophysical signatures including leftward-shifted
  activation, faster activation kinetics, and delayed deactivation. These
  changes increase channel open probability at near-resting potentials,
  disrupting neuronal excitability and potentially affecting primary cilia
  biology and Hedgehog signaling pathways important for ectodermal development.
  Maternal mosaicism with milder phenotypes (epilepsy only) has been documented,
  highlighting the importance of parental testing in genetic counseling.
  Comparative studies of related EAG-family channels (KCNH5) support a conserved
  gain-of-function pathomechanism across this channel family.
clinical_trials:
- name: NCT06380192
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >
    A French national retrospective natural history study collecting clinical data
    on patients with developmental and epileptic encephalopathy (DEE) of genetic
    etiology. By building a large-scale database of DEE patients stratified by
    genetic cause, this study aims to identify biomarkers, improve classification,
    and develop personalized management recommendations. KCNH1-related DEE patients
    would be eligible for inclusion.
  target_phenotypes:
  - preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: clinicaltrials:NCT06380192
    supports: SUPPORT
    snippet: "The creation of a database with retrospective follow-up of a large number of patients on a national scale will enable better knowledge of specific biomarkers, and thus a better classification and understanding of the natural evolution of DEE according to their etiology."
    explanation: Natural history study for genetically-caused DEE could include KCNH1/Temple-Baraitser patients, providing data on disease progression and biomarkers for this ultra-rare condition.
- name: NCT06700811
  phase: PHASE_I
  status: RECRUITING
  description: >
    A single-center pilot study evaluating the safety and feasibility of early
    ketogenic diet administration to prevent epileptic spasms in infants with
    genetic seizure disorders. Ketogenic diet is an established non-medication
    treatment for difficult-to-control seizures. Infants with KCNH1-related
    genetic epilepsy could qualify for this preventive intervention approach.
  target_phenotypes:
  - preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: clinicaltrials:NCT06700811
    supports: SUPPORT
    snippet: "Epileptic spasms (ES) are a predominantly infantile seizure type observed frequently in certain genetic disorders. Ketogenic diet (high ratio of fat to carbohydrate/protein) is an established non-medication treatment for difficult to control seizures, including ES."
    explanation: Pilot trial of ketogenic diet for prevention of epileptic spasms in genetic epilepsies is relevant to the infantile-onset seizures characteristic of Temple-Baraitser syndrome.
- name: NCT06278428
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >
    An observational study examining the genotype-phenotype correlations and
    disease progression of developmental epileptic encephalopathy with onset
    before 2 years of age. The study follows patients for 2 years to characterize
    the natural history of genetically-caused DEE, which is directly relevant to
    understanding the early course of KCNH1-related encephalopathy.
  target_phenotypes:
  - preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: clinicaltrials:NCT06278428
    supports: SUPPORT
    snippet: "Children with epileptic and developmental encephalopathy due to genetic causes are at higher risk of developing neurodevelopmental disorders than children with epileptic and developmental encephalopathy due to other causes."
    explanation: Study of genotype-phenotype correlations in early-onset DEE is relevant to understanding disease progression in KCNH1-related encephalopathy, where seizures typically begin in infancy.
classifications:
  harrisons_chapter:
  - classification_value: nervous system disorder
  - classification_value: epilepsy
  - classification_value: hereditary disease
  channelopathy_category:
    classification_value: neurological channelopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012735
      label: Temple-Baraitser syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease term for this entry.
datasets: