Clinical characteristics.

KCNQ3-related disorders include benign familial neonatal epilepsy (BFNE) and benign familial infantile epilepsy (BFIE), seizure disorders that occur in children who typically have normal psychomotor development. An additional KCNQ3-related disorder involves developmental disability.

• In BFNE seizures begin in an otherwise healthy infant between days two and eight of life and spontaneously disappear between the first and the sixth to 12th month of life. Seizures are generally brief, lasting one to two minutes. Seizure types include tonic or apneic episodes, focal clonic activity, and autonomic changes. Motor activity may be confined to one body part, migrate to other regions, or generalize. Infants are well between seizures and feed normally.
• In BFIE seizures start in the first year of life, beyond the neonatal period, and disappear after age one to two years. Seizures are generally brief, lasting two minutes; they appear as daily repeated clusters. Seizure type is usually focal, but can be also generalized, causing diffuse hypertonia with jerks of the limbs, head deviation, or motor arrest with unconsciousness and cyanosis. Infants are normal between seizures and psychomotor development is usually normal.
• In the KCNQ3-related developmental disability phenotype, individuals present with intellectual disability with or without seizures and/or cortical visual impairment. As little clinical information on these individuals is available, the clinical presentation of KCNQ3-related developmental disability remains to be defined.

Diagnosis/testing.

The diagnosis of a KCNQ3-related disorder is established in an individual with typical clinical findings and the presence of a heterozygous pathogenic variant in KCNQ3.

Management.

Treatment of manifestations: The seizures of BFNE are generally controlled with anti-seizure medication (ASM) including phenobarbital and phenytoin or carbamazepine, which is usually withdrawn at age three to six months. The seizures of BFIE are usually completely controlled with adequate doses of phenobarbital, carbamazepine, or valproate. In the rare instance of seizure recurrence, the starting dose of ASM is often low. ASMs are usually withdrawn after one to three years. KCNQ3-related developmental disability is managed using standard evaluations, therapies, and educational support tailored to the individual’s needs.

Surveillance: In children with BFNE, EEGs at age three, 12, and 24 months are recommended; the EEG at 24 months should be normal. In children with BFIE, EEGs at onset, 12, 24 and 36 months are recommended; the EEG at 36 months should be normal.

Pregnancy management: The management of a pregnant woman with a KCNQ3 pathogenic variant is the same as that for any other pregnant woman with a seizure disorder or at increased risk for a seizure disorder: (a) no ASM is required if the woman has been seizure-free or if the woman has no history of seizures; and (b) ASM may be continued for epilepsy that is active during pregnancy.

Genetic counseling.

The KCNQ3-related disorders BFNE and BFIE are inherited in an autosomal dominant manner and most individuals diagnosed with KCNQ3-related BFNE and KCNQ3-related BFIE have an affected parent or a parent known to have been symptomatic in infancy. In contrast, all individuals with KCNQ3-related developmental disability reported to date have the disorder as the result of a de novo KCNQ3 pathogenic variant. Each child of an individual with BFNE or BFIE has a 50% chance of inheriting the pathogenic variant. If the KCNQ3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible.

Suggestive Findings

KCNQ3-related benign familial neonatal epilepsy (BFNE) and benign familial infantile epilepsy (BFIE) should be suspected in individuals with the following findings.

Benign familial neonatal epilepsy (BFNE)

• Seizures starting in an otherwise healthy infant between days two and eight of life and spontaneously disappearing between the first and the sixth to12th month of life
• Normal physical examination and laboratory tests prior to onset of seizures, between seizure episodes, and following cessation of seizures
• No specific EEG criteria, but EEG background is normal or near normal for age
• Family history of the same findings usually present

Seizure features include the following [ILAE 1989, Ronen et al 1993, Engel 2001]:

• A wide spectrum of seizure types, encompassing tonic or apneic episodes, focal tonic (stiffening) or clonic (rhythmic shaking) activity, or autonomic changes
• Motor activity that may be confined to one body part, migrate to other body regions, or generalize
• Seizures that are usually brief, lasting one to two minutes
• Infants who are well between seizures and feed normally
• Interictal EEG that may be normal
• Ictal EEG showing focal onset with possible secondary generalization

The diagnosis of KCNQ3-related BFNE is suspected in individuals with clinical findings consistent with BFNE and normal results on testing of KCNQ2, the main locus for BFNE (see KCNQ2-Related Disorders).

Benign familial infantile epilepsy (BFIE)

• Brief, repeated, focal, and secondarily generalized seizures occur in otherwise healthy infants; seizures occur in a rather wide time frame in the first year of life beyond the neonatal period.
• Seizures spontaneously disappear after age 1-2 years without neurologic sequelae in adulthood.
• Family history of the same findings is usually present.

The diagnosis of KCNQ3-related BFIE is suspected in individuals with clinical findings consistent with BFIE and normal results on testing of PRRT2, the main locus for BFIE (see PRRT2-Associated Paroxysmal Movement Disorders).

Developmental disability, which can present as one or more of the following:

• Epileptic encephalopathy, in which aggressive epileptogenic activity during brain maturation triggers progressive cognitive and neuropsychological deterioration or regression
• Intellectual disability apparently without epilepsy
• Intellectual disability with seizures and cortical visual impairment

Note: A few individuals presenting with the developmental disability phenotypes and a de novo pathogenic variant in KCNQ3 have been described in the literature. So far, very little clinical information on these individuals is available; thus, the clinical presentation of KCNQ3-related developmental disability remains to be defined.

Establishing the Diagnosis

The diagnosis of a KCNQ3-related disorder is established in a proband with typical clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in KCNQ3 identified by molecular genetic testing (see Table 1).

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings of benign familial neonatal epilepsy (BFNE) or benign familial infantile epilepsy (BFIE) as described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1). Because the phenotypic range of the KCNQ3-related developmental disorders is, at present, broad and somewhat nonspecific, this is more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The KCNQ3-related disorders include benign familial neonatal epilepsy (BFNE) and benign familial infantile epilepsy (BFIE), seizure disorders that occur in children who have structurally normal brains, normal interictal neurologic examinations, and normal psychomotor development. A more recently reported KCNQ3-related disorder is associated with a developmental disability phenotype.

KCNQ3-related benign familial neonatal epilepsy (BFNE) is characterized by seizures that start in an otherwise healthy infant between days two and eight of life and spontaneously disappear between age one month and age six to 12 months. Seizures are generally brief, lasting one to two minutes. Seizure types include tonic or apneic episodes, focal clonic activity, and autonomic changes. Motor activity may be confined to one body part, migrate to other regions, or generalize.

Infants are well between seizures and feed normally. Psychomotor development is usually normal. However, two individuals within the family with KCNQ3-related BFNE described by Soldovieri et al [2014] and three individuals in the family described by Miceli et al [2015b] showed (in addition to seizures) intellectual disability. Notably, although intellectual and/or language developmental delay has not been thought characteristic of BFNE, some recent reports highlight evidence for such variable expressivity in KCNQ2-related BFNE pedigrees as well [Millichap et al 2016, Al Yazidi et al 2017, Hewson et al 2017].

KCNQ3-related benign familial infantile epilepsy (BFIE) is characterized by seizures that start in the first year of life, beyond the neonatal period, and disappear after age one to two years. Seizures are generally brief, lasting about two minutes; they appear as daily repeated clusters. Seizure type is usually focal, but can be also generalized, causing diffuse hypertonia with jerks of the limbs, head deviation, or motor arrest with unconsciousness and cyanosis. Infants are normal between seizures and psychomotor development is usually normal.

KCNQ3-related developmental disability. Recent efforts to identify genetic contributions in a diversity of neurodevelopmental disorders using exome sequencing have identified a small number of individuals with de novo pathogenic missense variants in KCNQ3 [Allen et al 2013, McRae et al 2017]. Very little clinical information on these individuals is provided in these reports, but presentations include epileptic encephalopathy with progressive cognitive and neuropsychological deterioration or regression, intellectual disability without epilepsy, and intellectual disability with seizures and cortical visual impairment.

Note: During the same recent period, more than 100 individuals with developmental disability and missense variants in the close homolog, KCNQ2, have been described [Millichap et al 2016, Olson et al 2017]. Owing to very low numbers and incomplete phenotypic descriptions available to date, it may be suspected that pathogenic variants in KCNQ3 are very rare causes of developmental disability, but more detailed reporting of additional affected individuals is needed to clarify this.

Genotype-Phenotype Correlations

Because relatively few families heterozygous for a KCNQ3 variant have been reported to date, genotype-phenotype correlations are difficult to establish. In fact, no obvious phenotypic difference is seen between those families with variants that cause a 20%-40% reduction in KCNQ3 function and those that cause a more than 60% reduction in KCNQ3 function (see Molecular Pathogenesis).

Notably, four different studies have identified the p.Arg230Cys variant in children with developmental disability, apparently both with and without epilepsy [Rauch et al 2012, Allen et al 2013, Bosch et al 2016, McRae et al 2017].

See Table 2 for available genotype-phenotype information.

Penetrance

In KCNQ3-related BFNE, penetrance is incomplete (0.8-0.85): BFNE is found in 47 of 54 individuals with a KCNQ3 pathogenic variant [Charlier et al 1998, Hirose et al 2000, Singh et al 2003, Li et al 2006, Li et al 2008, Neubauer et al 2008, Fister et al 2013, Allen et al 2014, Soldovieri et al 2014, Grinton et al 2015, Miceli et al 2015b, Maljevic et al 2016, Sands et al 2016].

The finding of incomplete penetrance in KCNQ3-related BFNE and BFIE may result from failure to recognize the seizures (which can be brief and disappear spontaneously very soon after onset) in some individuals.

Penetrance has not been studied in KCNQ3-related developmental disability as few individuals have been reported, and those reported have had a de novo pathogenic variant. As in other severe developmental disorders, including KCNQ2-related epileptic encephalopathy, pathogenic variants are judged likely to be fully penetrant. Evidence for this comes by analogy from KCNQ2 pedigrees where parents who have postzygotic mosaicism for a pathogenic variant are asymptomatic or have mild symptoms similar to BFNE, but their heterozygous offspring have epileptic encephalopathy [Weckhuysen et al 2012, Milh et al 2015].

Nomenclature

Rett & Teubel [1964] were the first to report familial occurrence of neonatal seizures of presumed genetic (rather than acquired) origin. To highlight the mostly favorable outcome of the syndrome, the term "benign" was added to "familial neonatal convulsions" four years later by Bjerre & Corelius [1968]. Terminology was further revised to benign familial neonatal epilepsy (BFNE) to reflect the fact that the seizures were often focal and for consistency with naming of other epilepsy syndromes [Berg et al 2010].

Prevalence

Fewer than 20 families with BFNE (54 individuals) with a heterozygous KCNQ3 pathogenic variant have been reported to date [Charlier et al 1998, Hirose et al 2000, Singh et al 2003, Li et al 2006, Li et al 2008, Neubauer et al 2008, Fister et al 2013, Allen et al 2014, Soldovieri et al 2014, Grinton et al 2015, Miceli et al 2015b, Maljevic et al 2016, Sands et al 2016].

Only three families with BFIE (7 individuals) with a heterozygous KCNQ3 pathogenic variant have been reported to date [Singh et al 2003, Zara et al 2013, Fusco et al 2015].

The percentage of families with BFNE who have pathogenic variants in KCNQ3 is likely less than 5%, as KCNQ2 is the main locus for BFNE, accounting for more than 70% of cases (see KCNQ2-Related Disorders). No data on the prevalence of KCNQ3 pathogenic variants in BFIE are available; nevertheless, this figure is likely to be small given that another gene (PRRT2) is the main locus for BFIE.

Benign Familial Neonatal Epilepsy (BFNE)

The diagnosis of BFNE requires the absence of any other explanation for the seizures. No specific EEG trait characterizes BFNE during neonatal seizures; the interictal EEG is most commonly normal (50%-70% of infants).

Laboratory tests and imaging studies are important to exclude other possible causes for the seizures including those without a genetic etiology. It is important not to miss a diagnosis of a treatable meningoencephalitis in the early stages or of intracranial hemorrhage – for either, neonates do not exhibit the typical findings observed in older infants and children, and seizures may be the only early manifestation.

The following laboratory, imaging, and instrumental studies may be helpful for the differential diagnosis.

To detect infection or bleeding disorder:

• Basic hematologic labs. CBC, prothrombin time, activated partial thromboplastin time
• Lumbar puncture. Cerebrospinal fluid examination to exclude neonatal meningoencephalitis or occult blood
• MRI or CT scan of the brain. One or both of these tests should be performed in every individual with neonatal seizures to exclude structural lesions and intracranial hemorrhage.

To detect a biochemical disorder:

• Basic metabolic panel plus serum concentration of calcium, magnesium, phosphorus
• Evaluation of alpha-AASA levels in serum and urine as a biomarker of pyridoxine (vitamin B₆)-dependent seizures, a rare genetic disorder of vitamin B₆ metabolism caused by pathogenic variants in ALDH7A1 and characterized by neonatal-onset seizures that are resistant to common anticonvulsants, but controlled by daily treatment with vitamin B₆
• Thyroid function tests, as neonatal hyperthyroid state and thyrotoxicosis may be associated with excessive tremor and jitteriness ‒ clinical conditions which should be differentiated from seizures

Genetic testing. The most common cause of BFNE is a heterozygous pathogenic variant in KCNQ2 which – like KCNQ3 – encodes voltage-gated potassium channel subunits (see KCNQ2-Related Disorders). The frequency of KCNQ2 pathogenic variants as a cause of BFNE is more than tenfold that of KCNQ3 pathogenic variants.

Because the clinical characteristics of BFNE caused by a heterozygous pathogenic variant of KCNQ2 or KCNQ3 do not appear to differ, molecular genetic testing of both genes is commonly performed when BFNE is suspected.

Benign Familial Infantile Epilepsy (BFIE)

BFIE is genetically distinct from BFNE, with at least three loci additional to KCNQ3 being involved.

• In the largest fraction of affected families, the associated gene is PRRT2, a presynaptic protein interacting with SNAP-25 [Heron et al 2012, Zara et al 2013] (see PRRT2-Associated Paroxysmal Movement Disorders). Whereas some patients with pathogenic variants in PRRT2 develop paroxysmal kinesigenic dyskinesia later in life, clinical characteristics early in life do not differ from BFIE caused by pathogenic variants in KCNQ3.
• Less commonly, the associated gene is SCN2A, encoding one of the main pore-forming subunits of neuronal voltage-gated sodium channels [Striano et al 2006] (OMIM 607745). The clinical characteristics do not differ from those of KCNQ3-related BFIE.
• Additional families with a comparable phenotype show linkage to 19q12-q13.1 [Guipponi et al 1997]. The responsible gene is as yet unknown.

Developmental Disability

Phenotypic features associated with KCNQ3 pathogenic variants are so far not sufficiently defined to diagnose a KCNQ3-related disorder with a developmental disability phenotype. Therefore, all genes known to be associated with developmental disability (>180 have been identified) should be included in the differential diagnosis of KCNQ3-related disorders. Since the pathogenic variants associated with this specific KCNQ3-related phenotype are de novo (and thus have a negative family history), all inheritance patterns of developmental disability could be possible. See OMIM Phenotypic Series:

• Intellectual Developmental Disorder, Autosomal Dominant
• Intellectual Developmental Disorder, Autosomal Recessive
• Intellectual Developmental Disorder, Nonsyndromic, X-Linked

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a KCNQ3-related disorder, the following evaluations are recommended:

• In-depth neurologic examination
• Developmental evaluation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Benign familial neonatal epilepsy (BFNE). The seizures of BFNE are generally controlled with conventional anti-seizure treatment. Phenobarbital and phenytoin (loading doses of 15-20 mg/kg; maintenance doses of 3-4 mg/kg for both agents) [Painter et al 1981] are the anti-seizure medications (ASMs) most commonly used to treat neonatal seizures.

Because of concerns over the suboptimal effectiveness and safety of phenytoin and phenobarbital, other anticonvulsants (e.g., levetiracetam and topiramate) are often used in neonates with refractory seizures, despite limited data and off-label use [Tulloch et al 2012]. However, refractory seizures are uncommon in KCNQ3-related BFNE.

A recent study has been performed to evaluate treatment responses in a small cohort of 19 individuals presenting with clinical features suggestive of BFNE. All but three had family histories of neonatal seizures. Of the 19 individuals, pathogenic variants in KCNQ2 were found in 14; pathogenic variants in KCNQ3 were present in two. Seventeen (88%) of 19 individuals were seizure free within hours of receiving oral carbamazepine (CBZ) or oxcarbazepine (OXC). Earlier initiation of CBZ was associated with shorter hospitalization. No side effects of CBZ were reported. All individuals had normal development and remain seizure free at a mean follow-up period of six months to 16 years (mean: 7.8 years). The authors concluded that CBZ is safe and rapidly effective in neonates with BFNE, even in status epilepticus, and that CBZ should be the drug of choice in benign familial neonatal seizures [Sands et al 2016].

Interictal EEG is generally normal and does not influence treatment duration.

Anti-seizure medication is usually withdrawn at age three to six months.

Benign familial infantile epilepsy (BFIE). The seizures of BFIE are usually completely controlled with the anti-seizure medications phenobarbital, carbamazepine, or valproate. If adequately treated, very few individuals show recurrent seizures; seizure recurrence is often caused by a low starting dose of ASMs.

Anti-seizure medication is usually withdrawn after one to three years with no relapses.

Prevention of Secondary Complications

The potential complications of the disease treatment are those related to ASM use.

Surveillance

BFNE. EEG at onset, age three, 12, and 24 months is recommended. The EEG at 24 months should be normal.

BFIE. EEG at onset, 12, 24, and 36 months is recommended. The EEG at 36 months should be normal.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The management of a pregnant woman with a KCNQ3 pathogenic variant is the same as that of any other pregnant woman with a history of (or at risk for) epilepsy:

• No medication is indicated if (a) the woman has been seizure free and is not taking medication or (b) the woman has no history of seizures.
• Anti-seizure medication treatment may be continued for active epilepsy during pregnancy.
• In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].
• See MotherToBaby for more information on medication use during pregnancy.

Therapies Under Investigation

The selective neuronal KCNQ potassium channel opener ezogabine (US-approved name; retigabine in the EU and Canada), an ASM introduced in 2013 as adjunctive treatment of partial epilepsy in adults [Porter et al 2012], may represent a targeted therapy for KCNQ3-related seizures arising from variants that reduce channel activity. However, the discovery of additional side effects in the early post-marketing studies (blue discoloration of skin and retina) raised concerns about its use in children. Ezogabine has been commercially withdrawn as of June 2017.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

The KCNQ3-related disorders benign familial neonatal epilepsy (BFNE) and benign familial infantile epilepsy (BFIE) are inherited in an autosomal dominant manner. To date, all known cases of the KCNQ3-related developmental disability phenotype have been associated with de novo pathogenic variants.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with KCNQ3-related BFNE and KCNQ3-related BFIE have an affected parent or a parent who is known to have been symptomatic in infancy. Of note, parents can be heterozygous for a KCNQ3 pathogenic variant but have never been symptomatic, given that penetrance is incomplete or neonatal seizures may have been unrecognized as they are typically brief and disappear spontaneously soon after onset.
• In contrast, to date, individuals with KCNQ3-related developmental disability have the disorder as the result of a de novo KCNQ3 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the KCNQ3 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband, germline mosaicism in a parent, or low-level postzygotic mosaicism in the parent below the sensitivity of the test.
• The family history of some individuals diagnosed with KCNQ3-related BFNE and KCNQ3-related BFIE may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance. An initial, apparently negative family history may be regarded as uncertain until additional efforts are made to determine the early history of each parent including review of parents’ medical records, and, if possible, consultation with older relatives to determine if the parent was affected in infancy (but was unaware of the diagnosis as the phenotype did not persist beyond infancy). Therefore, an apparently negative family history for a proband with KCNQ3-related BFNE and KCNQ3-related BFIE cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have postzygotic mosaicism for the variant and may be mildly/minimally affected or asymptomatic. While this has been reported in KCNQ2-related BFNE [Weckhuysen et al 2012, Milh et al 2015], it has not been found in KCNQ3-related disorders to date.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%. Given the rarity of the disease, little is known about the inter- and intrafamilial phenotypic variability. In most families with KCNQ3 pathogenic variants, affected members showed a benign disease course. However, in the family described by Soldovieri et al [2014] febrile seizures beyond the neonatal period and intellectual deficiency occurred in two of the four affected family members, and in the family described by Miceli et al [2015b] three of the four affected individuals showed intellectual deficits in addition to seizures.
• If the parents have been tested for the KCNQ3 pathogenic variant identified in the proband and:
  • A parent of the proband has the KCNQ3 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • The KCNQ3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
• If the parents have not been tested for the KCNQ3 pathogenic variant but are clinically unaffected (and are known not to have been affected in infancy or childhood), the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for a KCNQ3-related disorder because of the possibility of reduced penetrance in a parent or the possibility of parental germline or low-level postzygotic mosaicism.

Offspring of a proband. Each child of an individual with a KCNQ3-related disorder has a 50% chance of inheriting the KCNQ3 pathogenic variant. Given the rarity of the disease, little is known about the inter- and intrafamilial phenotypic variability.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the KCNQ3 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the KCNQ3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The KCNQ potassium channel gene subfamily consists of five members (KCNQ1-5), each encoding a subunit of a voltage-gated potassium channel. Each subunit shows distinct tissue distribution and subcellular localization, as well as biophysical, pharmacologic, and pathophysiologic properties [Soldovieri et al 2011].

KCNQ subunits, similar to other voltage-gated potassium channel subunits, include six transmembrane domains, with cytoplasmic N-terminal (short) and C-terminal (longer) regions. In neurons, KCNQ2, KCNQ3, KCNQ4, and KCNQ5 subunits (either as homomultimers or heteromultimers) represent the molecular basis of the M-current (I_KM), a K⁺-selective, noninactivating, and slowly activating/deactivating current [Brown & Adams 1980, Wang et al 1998], showing a critical role in spike-frequency adaptation and neuronal excitability control.

In addition to KCNQ3, all other KCNQ genes have a role in human genetic disease:

• KCNQ1. Long QT syndrome (LQTS-1) [Wang et al 1996], familial atrial fibrillation [Chen et al 2003], and the short QT syndrome [Bellocq et al 2004]
• KCNQ2. The main locus for BFNE, and a common cause for early infantile epileptic encephalopathy (See KCNQ2-Related Disorders.)
• KCNQ4. Expressed mainly in the cochlea and central auditory pathways, causing a rare form of nonsyndromic autosomal dominant hearing loss (DFNA2) [Kubisch et al 1999]
• KCNQ5. Widely distributed in brain, skeletal muscle, and smooth muscle. Pathogenic variants have been found in four unrelated individuals with intellectual disability, two of whom also have epilepsy [Lehman et al 2017].

Gene structure. The human KCNQ3 transcript has 16 exons.

At least four transcript variants are known; their functional roles and differences are unknown.

• Transcript variant 1 (NM_004519.3; 11266 bp) is the predominant isoform, containing 15 exons; it encodes isoform 1 of the KCNQ3 channel, consisting of 872 aa (NP_004510.1), and is by at least tenfold the most expressed form in all tissues.
• Several additional minor isoforms are generated by combinations of alternative first-exon use and alternative splicing of the 3’ exons.

For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The first pathogenic variant in KCNQ3 was described in 1998 [Charlier et al 1998]. Table 2 lists the variants currently associated with KCNQ3-related seizure disorders. Whenever possible, a short comment on the functional consequences of each variant is given, along with interpretation based on current understanding of the disorder.

Normal gene product. KCNQ3 encodes a voltage-gated potassium channel subunit (KCNQ3 or Kv7.3) mainly expressed in neurons. KCNQ3 appears unable to form a ion-conducting channel by itself, but must coassemble with KCNQ2, KCNQ4, or KCNQ5.

KCNQ3/KCNQ2 heteromers are believed to be the main constituents underlying a K⁺ current, called M-current, which plays important roles in controlling excitability in many central and peripheral neurons [Delmas & Brown 2005]. M-current activation reduces neuronal excitability by stabilizing the membrane potential at values closer to the equilibrium potential for K⁺ ions, thus limiting repetitive firing and contributing to spike frequency adaptation. M-current, somewhat paradoxically, can also augment excitability under some conditions, by enhancing availability of the sodium channels driving the neuronal action potential [Battefeld et al 2014]. M-currents are present on both excitatory principal cells and inhibitory interneurons [Lawrence et al 2006, Battefeld et al 2014]. The complexity of M-current roles, which may change with human development, are factors contributing to the phenotypic heterogeneity and age dependence associated with KCNQ3.

Abnormal gene product. Except for one small pedigree with an intragenic deletion [Sands et al 2016], all known pedigrees with KCNQ3-related epilepsy have missense variants. Heterozygous KCNQ3 complete loss may usually be tolerated, since there are 11 splice site, frame shift, and stop gain variants in the gnomAD control dataset. This stands in contrast to KCNQ2-related BFNE, where about two thirds of pedigrees have large intragenic deletions, splice site, frame shift, and stop gain variants [Millichap et al 2016], and only one such allele (also found in a large BFNE pedigree) is present in gnomAD. Thus, KCNQ3 pathogenicity appears usually to result from the expression of variant KCNQ3 subunits that alter the activity of heteromeric channels.

A series of missense KCNQ3 variants identified in BFNE pedigrees have been shown to reduce KCNQ2/KCNQ3 current, but the quantitative reduction does not appear to strictly correlate with seizure duration or presence of developmental disability. Most BFNE-causing KCNQ3 variants (e.g., p.Glu299Lys, p.Asp305Gly, p.Gly310Val, and p.Arg330Cys) caused a 20%-40% reduction in current, but expression of KCNQ3 p.Tyr309Arg reduced heteromeric channel function by about 60%, suggesting a dominant-negative effect. No obvious phenotypic differences were seen between those families. In addition, two KCNQ3 variants (p.Arg330Leu and p.Ile317Thr) described in pedigrees including individuals with BFNE symptoms in infancy but subsequent moderate psychomotor delay caused a variable decrease (between 30% and >60%) in aspects of channel function [Soldovieri et al 2014, Miceli et al 2015b].

The KCNQ3 variant p.Arg230Cys, recently identified as occurring de novo in four individuals with phenotypes including epileptic encephalopathy and intellectual disability with or without seizures and cortical visual impairment, is located outside the pore domain, in the voltage-sensor. Functional studies have demonstrated an opposite effect to variants causing BFNE. KCNQ3 variant p.Arg230Cys stabilized the channel open state, thereby producing a gain-of-function effect [Miceli et al 2015a]. Owing to small patient numbers, incomplete clinical information, and complex functional profiles of the known KCNQ3 variants, definitive conclusions about potential genotype-phenotype correlations cannot be drawn at this stage.

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Acknowledgments

The Authors acknowledge funding agencies for supporting their studies; in particular: Telethon GP15113, Italian Ministry for Education and Research (SIR RBSI1444EM), Citizens United for Research in Epilepsy, The Jack Pribaz Foundation, KCNQ2 Cure Alliance, and NINDS (NS49119). Collaborations from patients and their families are also highly appreciated.

Author History

Giulia Bellini, PhD; Second University of Naples (2014-2017)
Edward C Cooper, MD, PhD (2017-present)
Giangennaro Coppola, MD; University of Salerno (2014-2017)
Nishtha Joshi, BDS, MPH (2017-present)
Francesco Miceli, PhD (2014-present)
Emanuele Miraglia del Giudice, MD; Second University of Naples (2014-2017)
Maria Virginia Soldovieri, PhD (2014-present)
Maurizio Taglialatela, MD, PhD (2014-present)
Sarah Weckhuysen, MD, PhD (2017-present)

Revision History

• 7 September 2017 (ha) Comprehensive update posted live
• 22 May 2014 (me) Review posted live
• 26 September 2013 (mt) Original submission