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KCNK9 Imprinting Syndrome

Synonym: Birk-Barel Syndrome

, MD and , MD, ScD.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

KCNK9 imprinting syndrome is characterized by congenital central hypotonia (manifest as decreased movement, lethargy, and weak cry), severe feeding difficulties (resulting from facial weakness and poor suck), delayed development/intellectual disability, and dysmorphic manifestations. Poor feeding can cause failure to thrive during infancy unless managed appropriately. Significant dysphagia of solid foods typically persists until puberty. Intellectual disability can be severe. To date 19 individuals with a molecularly confirmed diagnosis have been reported.

Diagnosis/testing.

The diagnosis of the KCNK9 imprinting syndrome is established in a proband with suggestive clinical findings and detection of the heterozygous KCNK9 pathogenic variant p.Gly236Arg on the maternal allele.

Management.

Treatment of manifestations: A multidisciplinary team of specialists in clinical genetics, plastic surgery, ophthalmology, pulmonology, gastroenterology, feeding, endocrinology, and neurology is recommended (depending on the individual’s needs). Standard treatment for lacrimal duct obstruction, obstructive sleep apnea, scoliosis, and seizures. Feeding problems typically require use of special nipples and/or bottles and/or nasogastric/gastrostomy tube feedings. Cleft palate and velopharyngeal insufficiency are managed as per standard practice as are developmental delay/intellectual disability. Transient neonatal hypoglycemia responds to diazoxide treatment.

Surveillance: Monitoring of serum glucose levels for hypoglycemia in the neonatal period. At least annual ophthalmology evaluation, monitoring for the development of scoliosis, and monitoring of nutritional status, growth, and feeding.

Genetic counseling.

KCNK9 imprinting syndrome is inherited in an autosomal dominant maternally imprinted manner (i.e., a heterozygous pathogenic variant on the maternally derived KCNK9 allele results in disease; a pathogenic variant on the paternally derived KCNK9 allele does not result in disease because normally the paternally derived KCNK9 allele is silenced). The KCNK9 pathogenic variant can either be inherited from the mother (80%) or arise de novo on the maternally derived KCNK9 allele (20%). The risk to the sibs of the proband depends on the genetic status of their mother: if she is heterozygous for the KCNK9 pathogenic variant, the risk to the sibs is 50%; if the KCNK9 pathogenic variant cannot be detected in her leukocyte DNA, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism. To date, no individual with KCNK9 imprinting syndrome has been known to reproduce. Once the KCNK9 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for KCNK9 imprinting syndrome (i.e., one in which the mother is heterozygous for a KCNK9 pathogenic variant) and preimplantation genetic diagnosis are possible.

Diagnosis

Consensus clinical diagnostic criteria for the KCNK9 imprinting syndrome have not been established.

Suggestive Findings

KCNK9 imprinting syndrome should be suspected in individuals with normal brain imaging and the following clinical findings:

  • Congenital central hypotonia and persistent generalized weakness
  • Severe feeding difficulties, often requiring placement of gastrostomy tube.
  • Delayed development/ intellectual disability

Establishing the Diagnosis

The diagnosis of the KCNK9 imprinting syndrome is established in a proband with suggestive clinical findings and the heterozygous KCNK9 p.Gly236Arg pathogenic variant on the maternal allele detected by molecular genetic testing (see Table 1). To date, it is unknown if other KCNK9 pathogenic variants can cause the same phenotype.

Because the phenotype of the KCNK9 imprinting syndrome is indistinguishable from many other inherited disorders with hypotonia, feeding difficulties, and developmental delay/intellectual disability, molecular genetic testing approaches can include genomic testing (comprehensive genomic sequencing) OR gene-targeted testing (multi-gene panel). Note that gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not.

  • Comprehensive genomic sequencing (when available) including exome sequencing and genome sequencing can be considered. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
  • A multi-gene panel that includes KCNK9 and other genes of interest (see Differential Diagnosis) can be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in KCNK9 Imprinting Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
KCNK9Sequence analysis 3, 49/9
Gene-targeted deletion/duplication analysis 50/9
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Since KCNK9 is a maternally expressed imprinted gene, determining whether a variant is maternally or paternally inherited is critical for variant classification.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

KCNK9 imprinting syndrome is characterized by congenital central hypotonia, severe feeding difficulties, delayed development/intellectual disability, and dysmorphic features. To date 19 individuals with a molecularly confirmed diagnosis have been reported: 15 from an Arab-Israeli family [Barel et al 2008] and four representing simplex cases (i.e., a single occurrence in a family) [Graham et al 2016]. Note that 15 individuals from the original family were reexamined for the report by Graham et al [2016].

The phenotype has been severe and consistent in all individuals examined to date.

Congenital central hypotonia, evident in neonates, is associated with decreased movement, lethargy, weak cry, weak facial muscles, poor suck, and feeding difficulties. Prenatally, hypotonia can manifest as decreased fetal movement and breech presentation necessitating cesarean section.

While the hypotonia may improve over time, it is present during childhood and into adulthood. Occasionally weakness of proximal muscles and the supra- and infrascapular and trapezius muscles is observed later in life. Generalized hypotonia at an early age followed by weakness of proximal muscles can lead to contractures and scoliosis.

Poor feeding can cause failure to thrive during infancy unless managed appropriately (see Management). Significant dysphagia of solid foods due to hypotonia and poorly coordinated swallowing typically persists until puberty [Barel et al 2008].

Cleft palate (including full cleft, submucous cleft or velopharyngeal insufficiency) is present in 42% of affected individuals.

Delayed motor and speech milestones / intellectual disability are observed in all individuals with the KCNK9 imprinting syndrome. Intellectual disability is usually moderately severe with limited speech. Wide-based gait can also be observed.

Other

Occasional neurologic findings include clonus and rarely seizures.

Subtle dysmorphic features that can evolve over time include dolichocephaly with a narrow forehead; mild atrophy of the temporalis and masseter muscles; myopathic elongated facies with a tented vermillion of the upper lip and short broad philtrum; reduced facial movement; mild micro/retrognathia with relatively prominent maxillary and premaxillary regions; medially flared, arched eyebrows; and ptosis [Graham et al 2016].

Body habitus is asthenic; a long neck and tapered chest are evident in later childhood. Fingers are tapered; fetal fingertip pads are prominent [Barel et al 2008].

A pilonidal dimple or sinus is evident in most individuals. Rarely, it is associated with a filar cyst (cystic structure in the proximal filum terminale) and lipoma in the sacral region.

Some affected individuals have transient neonatal hypoglycemia associated with hyperinsulinism that resolves with diazoxide treatment [Graham et al 2016].

Decreased lacrimation and increased risk for corneal dryness can be observed.

Sleep disturbance can be due to both central and obstructive sleep apnea, and usually responds to BiPAP.

Normal findings typically include: hearing, ophthalmologic evaluation (including vision), neuroimaging, and muscle biopsy (which may show nonspecific findings such as fiber-size disproportion). X-rays of long bones are normal [Barel et al 2008].

Penetrance

Penetrance for maternally inherited pathogenic variants in KCNK9 appears to be complete; however, the number of affected individuals with a molecularly confirmed diagnosis is so limited that no conclusions can be made at present.

Prevalence

KCNK9 imprinting syndrome has been identified in approximately 19 individuals, with most individuals from the original Arab-Israeli family reported by Barel et al [2008] having the same KCNK9 pathogenic variant. Since 2008 an additional four simplex cases (i.e., a single occurrence in a family) have been reported [Graham et al 2016].

Differential Diagnosis

A number of disorders can mimic some aspects of the KCNK9 phenotype. See Table 2.

Table 2.

Disorders to Consider in the Differential Diagnosis of KCNK9 Imprinting Syndrome

DisorderGenetic MechanismMOIClinical Features
Overlapping w/Those Seen in KCNK9 Imprinting SyndromeDistinguishing the Disorder from KCNK9 Imprinting Syndrome
Congenital myotonic dystrophy type 1>1000 CTG trinucleotide repeat expansion in DMPK 1AD
  • Hypotonia & severe generalized weakness at birth
  • Intellectual disability
  • Usually no cleft palate
Prader-Willi syndrome (PWS)Abnormal parent-specific imprinting within the Prader-Willi critical regionSee footnote 2
  • Severe hypotonia & feeding difficulties in early infancy
  • Delayed motor milestones & language development; some degree of cognitive impairment in all individuals
  • Hypotonia & feeding problems resolve more quickly
  • Usually no cleft palate
22q11.2 deletion syndromeDeletion of genes within the DiGeorge chromosome regionAD
  • Palatal abnormalities
  • Characteristic facial features
  • Learning difficulties
  • Immune deficiency
  • Hypocalcemia w/significant feeding & swallowing problems
  • Initial hypotonia less severe
  • Presence of heart defects
1.

Redman et al [1993] reported a few individuals with congenital myotonic dystrophy type 1 with repeats between 730 and 1000.

2.

PWS is caused by lack of expression of the paternally derived PWS/AS region of chromosome 15q11.2-q13 by one of several genetic mechanisms.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with KCNK9 imprinting syndrome, the recommended evaluations following diagnosis (if not performed as part of the evaluation that led to diagnosis) are summarized in Table 3.

Table 3.

Recommended Evaluations Following Initial Diagnosis of KCNK9 Imprinting Syndrome

SystemEvaluationComment
OropharynxAssessment by a cleft/craniofacial team if cleft palate, bifid uvula, or velopharyngeal insufficiency is present
FeedingFeeding & swallowing evaluationConsider gastrosotomy tube placement if clinically indicated by significant microretrognathia and/or recurrent aspiration
PulmonaryPolysomnogram if obstructive apnea is suspected
MusculoskeletalEvaluation for skeletal manifestations (i.e. joint contractures, scoliosis)Consider referral to an orthopedist, if indicated
NeurologicalAssessment of strength & motor skills
EEG if seizures are suspected
Spinal ultrasound of a pilonidal dimple or sinus to assess for filar cyst & lipoma in the sacral region
EndocrineAssessment for hypoglycemia during neonatal period & infancyIf present, consider consultation w/an endocrinologist to discuss possible treatment w/diazoxide
Misc/OtherDevelopmental assessment
Consultation w/a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No specific management guidelines have been developed. Management is mostly supportive.

A multidisciplinary team of specialists in clinical genetics, plastic surgery, ophthalmology, pulmonology, gastroenterology, feeding, endocrinology, and neurology is recommended depending on the affected individual’s manifestations.

Table 4.

Treatment of Manifestations in Individuals with KCNK9 Imprinting Syndrome

ManifestationTreatmentConsiderations/Other
Lacrimal duct obstructionTear duct massage; consider lacrimal duct stent placement
Cleft palate, bifid uvula, or velopharyngeal insufficiencyManagement by a cleft/craniofacial team; retrognathia & underdevelopment of the mandible may require mandibular distraction osteogenesis.
Obstructive sleep apneaCPAP or BiPAP; ENT evaluation for tonsillectomy/adenoidectomyPulmonary consultation; consider treatment w/mefanamic or flufenamic acid (see Therapies Under Investigation)
Feeding difficulties or signs of aspirationUse of a special nipple or bottle with cleft palate; short-term nasogastric feeding tube; consideration of gastrostomy tube
Gastroesophageal reflux diseaseStandard positioning & pharmacologic treatment
Musculoskeletal findings (i.e., contractures, scoliosis)Ankle-foot orthoses or other assistive devices; standard treatment for scoliosisPhysical therapy and/or occupational therapy evaluation; consultation w/an orthopedist
Seizure disorderEvaluation of blood sugar & electrolytes; standard treatment for seizuresConsider EEG and referral to a neurologist
Unexplained hypoglycemia or suspected hyperinsulinismConsideration of diazoxide therapyConsider referral to an endocrinologist
Developmental delayEarly referral for developmental support/special education, which may include physical therapy, occupational therapy, speech therapy, and/or cognitive therapyConsider referral to a neurodevelopmental specialist and/or neuropsychiatric testing

Surveillance

Table 5.

Recommended Surveillance for Individuals with KCNK9 Imprinting Syndrome

SystemEvaluationFrequency/Comment
GrowthEvaluation of nutritional status & growthEvery 6 months until age 2 years, then annually
EyesOphthalmology evaluation to assess for evidence of decreased lacrimation & increased risk for corneal drynessAt least annually
ENT/MouthEvaluation of feeding difficultiesEvery 6 months until age 2 years, then annually
RespiratorySleep study (if history of sleep disturbance)Pulmonary evaluation every 6 months until age 2 years, then annually
MusculoskeletalEvaluate for scoliosisAt least annually
EndocrineMonitor serum glucose levels to monitor for hypoglycemia secondary to poor feeding & increased risk for hyperinsulinemiaEvery 6 months until age 2 years

Evaluation of Relatives at Risk

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

Therapies Under Investigation

KCNK9, which is imprinted and expressed from the maternal allele with paternal silencing, encodes a member of the two pore-domain potassium channel (K2p9.1 or TASK3). The only KCNK9 pathogenic variant reported to date, p.Gly236Arg, reduces the outward current of the TASK3 channel by approximately 80% [Veale et al 2014].

Three members of the nonsteroidal anti-inflammatory fenamic acid class of drugs – flufenamic acid (FFA), niflumic acid (NFA) and mefanamic acid (MFA) – have been shown to stimulate two pore-domain potassium channels [Takahira et al 2005]. The reduced outward current through abnormal p.Arg236-containing TASK3 channels has been shown to be partially rescued by FFA, suggesting that fenamic acid compounds could be useful in treating this condition [Veale et al 2014].

Two affected individuals to date have been treated with oral MFA starting at age 14 months, with noted increased energy while on the medication and no adverse reactions. Clinical features are still present, and long-term studies are necessary to predict the outcome of individuals treated with MFA [Graham et al 2016].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

KCNK9 imprinting syndrome is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the maternally derived KCNK9 allele results in disease; a pathogenic variant on the paternally derived KCNK9 allele does not result in disease because normally the paternally derived KCNK9 allele is silenced). In any given affected individual, a pathogenic variant (typically p.Gly236Arg) that causes KCNK9 imprinting syndrome can either be inherited from the mother or arise de novo on the maternally derived KCNK9 allele.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s mother.
  • If the mother of the proband is heterozygous for the KCNK9 pathogenic variant, the risk to the sibs is 50%.
  • If the KCNK9 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism.

Offspring of a proband. To date, no individual affected with KCNK9 imprinting syndrome has been known to reproduce.

Other family members

  • The risk to other family members depends on the genetic status of the proband's mother.
  • If the proband’s mother is heterozygous for a KCNK9 pathogenic variant, other male and female family members may also be heterozygous for the pathogenic variant.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females heterozygous for a paternally inherited KCNK9 pathogenic variant.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the KCNK9 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for KCNK9 imprinting syndrome (i.e., one in which the mother is heterozygous for a KCNK9 pathogenic variant) and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

KCNK9 Imprinting Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for KCNK9 Imprinting Syndrome (View All in OMIM)

605874POTASSIUM CHANNEL, SUBFAMILY K, MEMBER 9; KCNK9
612292BIRK-BAREL MENTAL RETARDATION DYSMORPHISM SYNDROME

Gene structure. KCNK9 has five exons. This gene is also known in the literature as KT3.2, TASK3, and K2p9.1.

Pathogenic variants. The two maternally inherited pathogenic variants associated with the KCNK9 imprinting syndrome, c.770G>A and c.770G>C, both predict the protein change p.Gly236Arg.

Table 6.

KCNK9 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.770G>A and c.770G>Cp.Gly236ArgNM_001282534​.1
NP_001269463​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. KCNK9 (also called TASK3) is maternally expressed and encodes a member of the two pore-domain potassium channel (K2P) subfamily and functions as a pH-dependent potassium channel, known as TASK3 [Veale et al 2014, Graham et al 2016].

Because KCNK9 is an imprinted gene, the paternal allele is normally silenced; thus, a pathogenic variant on the maternal copy of KCNK9 causes disease, whereas a pathogenic variant on the paternal copy will have no effect.

TASK3 channels are found throughout the body, especially in the brain where they may play a role in the migration of cortical pyramidal neurons by regulating membrane potential and in action potential repolarization [Bando et al 2014, Graham et al 2016].

Abnormal gene product. The c.770G>C and c.770G>A (p.Gly236Arg) pathogenic variants reduce by 80% the functional currents of the TASK3 channels [Veale et al 2014]. Because granule neurons do not maintain sustained repetitive firing in the absence of TASK3 channels [Brickley et al 2007, Graham et al 2016], reduction in the activity of these channels alters both neuronal activity and neuronal development

References

Literature Cited

  • Bando Y, Hirano T, Tagawa Y. Dysfunction of KCNK potassium channels impairs neuronal migration in the developing mouse cerebral cortex. Cereb Cortex. 2014;24:1017–29. [PubMed: 23236211]
  • Barel O, Shalev SA, Ofir R, Chone A, Zlotogora J, Shorer Z, Mazor G, Finer G, Khateeb S, Zilberberg N, Birk OS. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am J Hum Genet. 2008;83:193–199. [PMC free article: PMC2495061] [PubMed: 18678320]
  • Brickley SG, Aller MI, Sandu C, Veale EL, Alder FG, Sambi H, Mathie A, Wisden W. TASK-3 two-pore domain potassium channels enable sustained high-frequency firing in cerebellar granule neurons. J Neurosci. 2007;27:9329–40. [PubMed: 17728447]
  • Graham JM Jr, Zadeh N, Kelley M, Tan ES, Liew W, Tan V, Deardorff MA, Wilson GN, Sagi-Dain L, Shalev SA. KCNK9 imprinting syndrome-further delineation of a possible treatable disorder. Am J Med Genet A. 2016;170:2632–7. [PubMed: 27151206]
  • Redman JB, Fenwick RG Jr, Fu YH, Pizzuti A, Caskey CT. Relationship between parental trinucleotide GCT repeat length and severity of myotonic dystrophy in offspring. JAMA. 1993;269:1960–5. [PubMed: 8464127]
  • Takahira M, Sakurai M, Sakurada N, Sugiyama K. Fenamates and diltiazem modulate lipid-sensitive mechano-gated 2P domain K(+) channels. Pflugers Arch. 2005;451:474–8. [PubMed: 16075240]
  • Veale EL, Hassan M, Walsh Y, Al-Moubarak E, Mathie A. Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Mol Pharmacol. 2014;85:397–407. [PubMed: 24342771]

Chapter Notes

Acknowledgments

Melissa Kelley

Revision History

  • 23 March 2017 (bp) Review posted live
  • 14 July 2016 (jmg) Original submission
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