Clinical characteristics.

KCNQ3-related disorders include self-limited familial neonatal epilepsy (SLFNE) and self-limited familial infantile epilepsy (SLFIE), seizure disorders that occur in children who typically have normal psychomotor development. An additional KCNQ3-related neurodevelopmental disorder (NDD) with and without epilepsy has also been described.

In KCNQ3-SLFNE, seizures begin in an otherwise healthy infant between age days two and eight of life and spontaneously disappear within the first year of life. Seizures are generally brief, lasting one to two minutes. Seizure types include tonic or apneic episodes and focal clonic activity, with or without autonomic changes. Motor activity may be confined to one body part, migrate to other regions, or generalize. Infants are normal between seizures and feed normally.

In KCNQ3-SLFIE, 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 types are usually focal, but can also include 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 KCNQ3-NDD, 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-NDD remains to be defined.

Diagnosis/testing.

The diagnosis of a KCNQ3-related disorder is established in a proband with suggestive findings and at least one heterozygous pathogenic variant in KCNQ3 identified by molecular genetic testing. Rarely, affected individuals have biallelic pathogenic variants in KCNQ3.

Management.

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controlled with anti-seizure medications (ASMs) including phenobarbital and phenytoin or carbamazepine, usually withdrawn at age three to six months.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 ASMs are usually withdrawn after one to three years.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

Surveillance: In children with KCNQ3-SLFNE, EEGs at onset and age three, 12, and 24 months are recommended; the EEG at 24 months should be normal. In children with KCNQ3-SLFIE, EEGs at onset and age 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: (1) no ASM is required if the woman has been seizure-free or if the woman has no history of seizures; and (2) ASM may be continued for epilepsy that is active during pregnancy.

Genetic counseling.

KCNQ3-SLFNE and KCNQ3-SLFIE are inherited in an autosomal dominant manner; most individuals have an affected parent, or a parent known to have been symptomatic in infancy. KCNQ3-NDD typically occurs as an autosomal dominant disorder caused by a de novo pathogenic variant. Rarely, KCNQ3-NDD is caused by biallelic pathogenic variants and inherited in an autosomal recessive manner.

Autosomal dominant inheritance: Each child of an individual with KCNQ3-SLFNE, KCNQ3-SLFIE, or autosomal dominant KCNQ3-NDD has a 50% chance of inheriting the pathogenic variant.

Autosomal recessive inheritance: If both parents of a child with autosomal recessive KCNQ3-NDD are known to be heterozygous for a KCNQ3 pathogenic variant, each sib of an affected individual has a 25% chance of being affected at conception, a 50% chance of being an asymptomatic carrier, and a 25% of being asymptomatic and not a carrier.

Once the KCNQ3 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

KCNQ3-related disorders should be suspected in individuals with the following clinical and laboratory findings (by phenotype), imaging findings, and family history.

KCNQ3-related self-limited familial neonatal epilepsy (KCNQ3-SLFNE)

• Clinical findings
  • Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element.
  • Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes.
  • Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures.
  • No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal.
• Laboratory findings. The diagnosis of KCNQ3-SLFNE is suspected in individuals with clinical findings consistent with SLFNE and normal results on molecular testing for KCNQ2, the main gene for SLFNE (see KCNQ2-Related Disorders).

KCNQ3-related self-limited familial infantile epilepsy (KCNQ3-SLFIE)

• Clinical findings
  • Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period.
  • Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood.
• Laboratory findings. The diagnosis of KCNQ3-SLFIE is suspected in individuals with clinical findings consistent with SLFIE and normal results on molecular testing for PRRT2, the main gene for SLFIE (see PRRT2-Associated Paroxysmal Movement Disorders).

KCNQ3-related neurodevelopmental disorder (KCNQ3-NDD), which can present as one or more of the following:

• Developmental delays or intellectual disability without epilepsy, with or without autism spectrum disorder
• Developmental delays or intellectual disability with epilepsy and cortical visual impairment, with or without autism spectrum disorder
• Developmental and epileptic encephalopathy (DEE), in which aggressive epileptogenic activity during brain maturation accompanies cognitive and neuropsychological stagnation or regression

Imaging findings. Brain MRI is usually normal.

Family history

• KCNQ3-SLFNE and KCNQ3-SLFIE. Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.
• KCNQ3-NDD. Because KCNQ3-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of a KCNQ3-related disorder is established in a proband with suggestive findings and at least one heterozygous pathogenic (or likely pathogenic) variant in KCNQ3 identified by molecular genetic testing (see Table 1). Rarely, some affected individuals have biallelic pathogenic (or likely pathogenic) variants in KCNQ3.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome 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 described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other epilepsy disorders are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, about 140 individuals have been identified with a pathogenic variant in KCNQ3 [Charlier et al 1998, Hirose et al 2000, Singh et al 2003, Li et al 2006, Li et al 2008, Neubauer et al 2008, Rauch et al 2012, Allen et al 2013, Fister et al 2013, Zara et al 2013, Allen et al 2014, Soldovieri et al 2014, Fusco et al 2015, Grinton et al 2015, Grozeva et al 2015, Miceli et al 2015b, Bosch et al 2016, Maljevic et al 2016, Sands et al 2016, Deciphering Developmental Disorders Study 2017, Ambrosino et al 2018, Kothur et al 2018, Lauritano et al 2019, Piro et al 2019, Sands et al 2019, Symonds et al 2019, Trinh et al 2019, Li et al 2020, Maghera et al 2020, Miceli et al 2020, Nardello et al 2020, Wang et al 2020, Miyake et al 2021, Arredondo et al 2022, Pijpers et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

KCNQ3-related disorders include self-limited familial neonatal epilepsy (SLFNE) and self-limited familial infantile epilepsy (SLFIE), seizure disorders that occur in children who have structurally normal brains, normal interictal neurologic examinations, and normal psychomotor development. Pathogenic variants in KCNQ3 have also been reported in individuals with neurodevelopmental disorders with or without epilepsy, expanding the known phenotypes.

KCNQ3-related self-limited familial neonatal epilepsy (KCNQ3-SLFNE) is characterized by seizures that start in an otherwise healthy infant between ages two and eight days of life and spontaneously disappear during the first year 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.

Psychomotor development is usually normal. However, two individuals within a family with KCNQ3-SLFNE described by Soldovieri et al [2014] and three individuals in another family reported by Miceli et al [2015b] showed (in addition to seizures) intellectual disability. Notably, although intellectual and/or developmental delays have not been considered characteristic of SLFNE, recent reports highlight evidence for variable expressivity in individuals with KCNQ2-SLFNE [Millichap et al 2016, Al Yazidi et al 2017, Hewson et al 2017].

KCNQ3-related self-limited familial infantile epilepsy (KCNQ3-SLFIE) 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 also be generalized, with jerking of the limbs, head deviation, and/or motor arrest with unconsciousness and cyanosis.

Infants are typically well between seizures and psychomotor development is usually normal.

KCNQ3-related neurodevelopmental disorder (KCNQ3-NDD). A small number of individuals with de novo pathogenic missense variants in KCNQ3 have been identified with neurodevelopmental disorder. De novo pathogenic variants in KCNQ3 have been described in a few children with intellectual disability and autism spectrum disorder with or without epilepsy [Rauch et al 2012, Allen et al 2013, Grozeva et al 2015, Miceli et al 2015b, Deciphering Developmental Disorders Study 2017, Sands et al 2019, Wang et al 2020, Miyake et al 2021] and cortical visual impairment [Bosch et al 2016]. Several of these children were reported to show sleep-activated epileptic activity on EEG, even in the absence of clinical seizures. Little clinical information on these individuals is provided in most of these reports; thus, the clinical presentation of KCNQ3-NDD remains to be defined in more detail. Biallelic pathogenic variants have been identified in three families with developmental and epileptic encephalopathy with neonatal-onset seizures and global developmental delay [Ambrosino et al 2018, Kothur et al 2018, Lauritano et al 2019].

Genotype-Phenotype Correlations

Pathogenic variants in KCNQ3 reported in typical familial forms of self-limited epilepsies (SLFNE and SLFIE) are commonly missense alterations located within the pore region (S5, S6, and intervening loop) and resulting in loss of function (LOF) of channel activity. Similar but more dramatic functional LOF effects have also been found in KCNQ3 channels carrying autosomal dominantly transmitted pathogenic variants responsible for more severe phenotypes, leading to the hypothesis that the degree of KCNQ3 functional impairment may contribute to clinical disease severity [Miceli et al 2015b]. Given the low number of pathogenic KCNQ3 variants described to date, definitive genotype-phenotype correlations are not very clear.

De novo missense alterations affecting the first two positively charged residues within the S4 transmembrane segment of the voltage-sensing domain (p.Arg227Gln, p.Arg230Cys/Ser/His) have been reported in individuals with developmental delay, autism spectrum disorder, and sleep-activated epileptiform discharges on EEG. Functional analysis using voltage clamp recordings revealed that these pathogenic variants stabilized the activated state of the channel and result in gain-of-function (GOF) effects on channel activity. In contrast to individuals with LOF pathogenic variants in KCNQ3, neonatal and infantile seizures were not a common finding in individuals with GOF pathogenic variants [Sands et al 2019]. More recent evidence confirms that these S4 variants in KCNQ3 are among the most recurrent in individuals with neurodevelopmental disorders [Wang et al 2020]. Additional KCNQ3 pathogenic variants are described in individuals with neurodevelopmental disorders; however, these variants have not been functionally assessed for whether they cause LOF or GOF [Wang et al 2020]. Biallelic LOF pathogenic variants have been described in three families and lead to a more severe phenotype of neonatal-onset epilepsy and global developmental delay [Ambrosino et al 2018, Kothur et al 2018, Lauritano et al 2019].

Penetrance

In KCNQ3-SLFNE, penetrance is incomplete (0.8-0.85): SLFNE is found in 72/80 (90%) of 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, Piro et al 2019, Symonds et al 2019, Maghera et al 2020, Miceli et al 2020, Pijpers et al 2023].

Incomplete penetrance in KCNQ3-SLFNE and KCNQ3-SLFIE may be due to failure to recognize the seizures (which can be brief and disappear spontaneously very soon after onset) in some individuals.

Penetrance in KCNQ3-NDD is little studied given the small number of reported individuals, but pathogenic variants with a proven functional effect are fully penetrant.

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 in contrast to other causes of recurrent neonatal seizures, the term "benign" was later added to "familial neonatal convulsions" 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 of naming with other epilepsy syndromes [Berg et al 2010].

In the most recent International League Against Epilepsy (ILAE) classification, the term "benign" is replaced by "self-limited" as a descriptor for epilepsy, referring to the likely resolution of the seizures during early infancy as well as good developmental outcome [Scheffer et al 2017]. Thus, the benign "familial" neonatal convulsion definitions previously adopted have been replaced by self-limited familial neonatal epilepsy (SLFNE) and self-limited familial infantile epilepsy (SLFIE).

Prevalence

About 20 families (72 individuals) with SLFNE 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, Piro et al 2019, Symonds et al 2019, Maghera et al 2020, Miceli et al 2020, Pijpers et al 2023]. The percentage of families with SLFNE who have pathogenic variants in KCNQ3 is likely less than 5%, as KCNQ2 is the main locus for SLFNE, accounting for more than 70% of cases (see KCNQ2-Related Disorders).

Only four families (8 individuals) with SLFIE and a heterozygous KCNQ3 pathogenic variant have been reported to date [Singh et al 2003, Zara et al 2013, Fusco et al 2015, Nardello et al 2020]. No data on the prevalence of KCNQ3 pathogenic variants in SLFIE are available; nevertheless, this figure is likely to be small given that PRRT2 is the main gene for SLFIE.

The prevalence of KCNQ3-NDD is unknown but the disorder seems to be rare. Pathogenic de novo variants in KCNQ3 are much less frequently identified than in its paralogue gene KCNQ2.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a KCNQ3-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Epilepsy in KCNQ3-related disorders – notably self-limited familial neonatal epilepsy (SLFNE) and self-limited familial infantile epilepsy (SLFIE) – are usually treatable using standard anti-seizure medication (ASM).

Targeted therapy. Most individuals with SLFNE or SLFIE caused by KCNQ3 pathogenic variants do not require therapy after seizure cessation. No targeted therapy is available for the most severe clinical phenotypes of KCNQ3-related disorders.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Prevention of Primary Manifestations

No specific primary prevention measure is available before symptom appearance.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

In individuals with known gain-of-function pathogenic variants in KCNQ3, the use of the potassium channel opener retigabine/ezogabine may be contraindicated.

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 (1) the woman has been seizure free and is not taking medications or (2) the woman has no history of seizures.
• Treatment with anti-seizure medication (ASM) 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 ASM during pregnancy reduces this risk. However, exposure to ASM 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 ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM 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 further information on medication use during pregnancy.

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

KCNQ3-related self-limited familial neonatal epilepsy (SLFNE) and KCNQ3-related self-limited familial infantile epilepsy (SLFIE) are inherited in an autosomal dominant manner.

In most individuals reported to date, KCNQ3-related neurodevelopmental disorder (NDD) occurs as an autosomal dominant disorder caused by a de novo pathogenic variant. Rarely, KCNQ3-NDD is caused by biallelic pathogenic variants and inherited in an autosomal recessive manner [Ambrosino et al 2018, Kothur et al 2018, Lauritano et al 2019].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with KCNQ3-SLFNE and KCNQ3-SLFIE 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 (or forgotten) as they are typically brief and disappear spontaneously soon after onset.
• In contrast, most individuals with autosomal dominant KCNQ3-NDD have the disorder as a result of a heterozygous de novo KCNQ3 pathogenic variant. (See Autosomal Recessive Inheritance – Risk to Family Members for discussion of KCNQ3-NDD caused by biallelic pathogenic variants.)
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with KCNQ3-SLFNE and KCNQ3-SLFIE 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 cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Given the rarity of KCNQ3-related disorders, little is known about the inter- and intrafamilial phenotypic variability. In most families with KCNQ3 pathogenic variants, affected members showed a self-limited 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 KCNQ3 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  Note: While parental mosaicism has not been reported in autosomal dominant KCNQ3-NDD to date, it is estimated that approximately 10% of individuals (who represent simplex cases) with any form of genetic developmental and epileptic encephalopathy have the disorder as the result of a pathogenic variant inherited from an asymptomatic mosaic parent [Myers et al 2018].
• If the parents have not been tested for the KCNQ3 pathogenic variant but are clinically unaffected and are known not to have had seizures in infancy or childhood, the risk to the sibs of a proband appears to be low. However, 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 and the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with an autosomal dominant KCNQ3-related disorder has a 50% chance of inheriting the KCNQ3 pathogenic variant.

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.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive KCNQ3-NDD are presumed to be heterozygous for a KCNQ3 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a KCNQ3 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a child with autosomal recessive KCNQ3-NDD are asymptomatic.

Sibs of a proband

• If both parents are known to be heterozygous for a KCNQ3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• The heterozygous sibs of a proband with autosomal recessive KCNQ3-NDD are asymptomatic.

Offspring of a proband.

• The offspring of an individual with autosomal recessive KCNQ3-NDD are obligate heterozygotes (carriers) for a pathogenic variant in KCNQ3.
• To date, individuals with autosomal recessive KCNQ3-NDD are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a KCNQ3 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the KCNQ3 pathogenic variants in the family.

Related Genetic Counseling Issues

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 known to have, or to be at risk of having, a KCNQ3 pathogenic variant.
• It is appropriate to offer KCNQ3 molecular genetic testing to the reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive KCNQ3-NDD, particularly if consanguinity is likely.

Prenatal Testing and Preimplantation Genetic Testing

Once the KCNQ3 pathogenic variant(s) have been identified in an affected family member, prenatal 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, like other voltage-gated potassium channel subunits, include six transmembrane domains, with cytoplasmic N- and C-terminal 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, non-inactivating, and slowly activating/deactivating current [Brown & Adams 1980, Wang et al 1998], showing a critical role in spike-frequency adaptation and neuronal excitability control.

KCNQ3 encodes a voltage-gated potassium channel subunit (KCNQ3 or Kv7.3) mainly expressed in neurons. In heterologous expression systems, currents carried by KCNQ3 homomeric channels are rather small, but are potentiated upon coexpression with KCNQ2 subunits. In the adult nervous system, KCNQ2/KCNQ3 heteromers are believed to be the main constituents of the M-current, a voltage-gated K⁺ current that 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 [Dirkx et al 2020].

Most KCNQ3-related epilepsy phenotypes are caused by single-nucleotide pathogenic variants, with a preponderance of missense variants. Heterozygous truncating variants in KCNQ3 have not been clearly associated with a disease phenotype, except for one report of an intragenic deletion affecting three individuals in a family [Sands et al 2016]. This is in contrast with KCNQ2, in which large intragenic deletions and splice site, frameshift, and stop gain pathogenic variants represent about two thirds of pedigrees of SLFNE [Millichap et al 2016]. Moreover, while homozygous deletions/frameshifts in KCNQ2 have never been reported, most likely because of their lethality, neonatal-onset epilepsy and developmental delay have been described in individuals carrying homozygous KCNQ3 frameshift variants, each inherited by an unaffected parent [Kothur et al 2018, Lauritano et al 2019]. In addition, one individual with early-onset developmental encephalopathy (DEE) with severe nonverbal cognitive impairment and spastic quadriparesis had two Kv7.3 missense variants (p.Val359Leu and p.Asp542Asn) in trans [Ambrosino et al 2018, Weckhuysen & George 2022]. Altogether, these data provide genetic evidence for the hypothesis that KCNQ3 pathogenic variants are better tolerated than KCNQ2 pathogenic variants in humans. In addition to the described pathogenetic mechanism, different developmental patterns of expression between the two genes (with KCNQ2 being expressed at earlier stages when compared to KCNQ3), as well as other factors such as inclusion/exclusion of both genes in panels for developmental and epileptic encephalopathy, diagnostic next-generation sequencing coverage, and epistatic compensation, may contribute to the lower incidence of epilepsy-associated variants described for KCNQ3 when compared with KCNQ2.

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 short QT syndrome [Bellocq et al 2004]
• KCNQ2. The main locus for SLFNE, 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 unrelated individuals with intellectual disability, two of whom also have epilepsy [Lehman et al 2017, Nappi et al 2022, Wei et al 2022].

Mechanism of disease causation

• KCNQ3-SLFNE and KCNQ3-SLFIE. Mild loss of function
• KCNQ3-NDD. Severe loss or gain of function

Author Notes

Sarah Weckhuysen ([email protected]) is actively involved in clinical research regarding individuals with KCNQ3-related neurodevelopmental disorders (NDD). She would be happy to communicate with persons who have any questions regarding diagnosis of KCNQ3-related NDD or other considerations.

Acknowledgments

The authors acknowledge funding from the following agencies for supporting their studies: the Italian Ministry for University and Research (MUR) (PRIN 2017ALCR7C), #NEXTGENERATIONEU (NGEU), National Recovery and Resilience Plan (NRRP), Project MNESYS (PE0000006 – A Multiscale Integrated Approach to the Study of the Nervous System in Health and Disease), the Italian Ministry of Health (Project GR-2016-02363337 and RF-2019-12370491), the European Commission H2020 (UNICOM – 875299), FWO (1861419N and G041821N), KCNQ2e.v., and the European Joint Programme on Rare Disease JTC 2020 (TreatKCNQ).

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

• 28 September 2023 (gm) Comprehensive update posted live
• 7 September 2017 (ha) Comprehensive update posted live
• 22 May 2014 (me) Review posted live
• 26 September 2013 (mt) Original submission

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