Clinical Diagnosis

The clinical spectrum of the KANSL1-related intellectual disability syndrome is variable. Besides developmental delay and intellectual disability, no single clinical feature is required to establish the diagnosis, although childhood hypotonia is a common feature, reported in almost all affected individuals.

Features that should prompt consideration of this diagnosis in an individual with developmental delay or intellectual disability include:

• Delayed speech
• Mild to moderate neonatal/childhood hypotonia
• Normal growth
• Epilepsy
• Dysmorphic facial features (see Figure 1):
  • Abnormal hair color/texture
  • Broad forehead and/or high anterior hairline
  • Ptosis
  • Blepharophimosis
  • Upward slanting palpebral fissures
  • Epicanthal folds
  • Large/prominent ears
  • Bulbous nose or tubular nose
  • Everted vermilion of the lower lip
• Heart anomalies
• Renal/urologic anomalies
• Hypermobility of the joints
• Hypermetropia
• Deformities of the feet and/or spine
• Friendly/amiable disposition

Figure

Figure 1. Photographs of eight different individuals with a 17q21.31 deletion

Testing

Cytogenetic testing. The 17q21.31 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Molecular Genetic Testing

Gene. KANSL1 is the only gene in which mutation is known to account for the majority of features of the syndrome [Koolen et al 2012b, Zollino et al 2012]

The KANSL1-related intellectual disability syndrome results from either of the following:

• Microdeletion of 17q21.31. The diagnosis of the KANSL1-related intellectual disability syndrome is confirmed by demonstration of a heterozygous deletion at chromosome 17q21.31 that includes KANSL1 [Koolen et al 2006, Sharp et al 2006, Shaw-Smith et al 2006]. Recently, it was shown that haploinsufficiency of KANSL1 is sufficient to cause the classic 17q21.31 microdeletion syndrome phenotype [Koolen et al 2012b, Zollino et al 2012].
• An intragenic KANSL1 mutation. To date, de novo KANSL1 mutations have been reported in six children with typical features of the KANSL1-related intellectual disability syndrome [Koolen et al 2012b, Zollino et al 2012, unpublished data].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in KANSL1-Related Intellectual Disability Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
KANSL1	Deletion / duplication analysis 2, 3	~600-kb deletion at 17q21.31 that includes KANSL1	~95% 4	Clinical
	Sequence analysis	Sequence variants 5	~5% 4
	Genotyping 6	Not applicable	Not applicable	Research only 7

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

3. Methods may be genomic microarrays or targeted. BAC or oligonucleotide arrays or genotyping arrays can detect the common deletion in a proband. Targeted methods including fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) can be used if the syndrome is suspected clinically or for confirmation of the deletion after genomic microarray analysis. Targeted approaches can also be used for evaluating relatives of the proband for presence of the deletion.

4. The majority of affected individuals are identified by a genome-wide CMA screen for deletions/duplications. CMA using BAC, oligonucleotide, or SNP genotyping arrays can detect the deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 17q21.3 region. It is too early to ascertain the frequency of the 17q21.31 microdeletion and a KANSL1 mutation. Given the fact that the chromosomal locus involved is flanked by segmental duplications, predisposing the locus to undergo deletion, it is likely that the recurrent microdeletion occurs more frequently.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

6. To date, testing in all unaffected parents from whom the deleted chromosome 17 originated has shown a 900-kb inversion involving chromosome 17q21.31. The frequency of this inversion (also referred to as the H2 lineage) in these parents is significantly greater than the approximately 20% frequency of the inversion found in the European population as a whole [Stefansson et al 2005] (p<10-5, Pearson’s Chi square test) [Koolen et al 2008]. Genotyping of parents for the H2 lineage is available on a research basis only. Testing for the inversion is not routinely indicated (see Molecular Genetics).

7. No laboratories offering clinical testing for this gene are listed in the GeneTests Laboratory Directory; clinical confirmation of mutations identified in a research laboratory may be available. See .

Interpretation of test results

• Deletion analysis. Depending on the initial test, validation of the deletion by an independent method may be warranted. If a high-density or targeted oligonucleotide genomic microarray platform that provides very dense coverage of the 17q21.31 region has been used for identification of the deletion, further validation may not be necessary, as it is unlikely that more than 50-100 adjacent DNA targets show an abnormal copy number by chance.
• Sequence analysis. For issues to consider in interpretation of sequence analysis results, click here.
  Note: Analysis of the genomic sequences can be difficult, as the mutant peak may be lower than expected because of the presence of low copy repeats in some individuals.

Testing Strategy

To establish the diagnosis in a proband requires detection of one of the following:

• A 17q21.31 microdeletion involving at least KANSL1
• A pathogenic mutation in KANSL1 (through sequence analysis)

Most deletions are detected by genomic chromosomal microarray (CMA) analysis performed as part of the evaluation of developmental delay or intellectual disability.

If the KANSL1-related intellectual disability syndrome is suspected based on clinical features, a targeted technique such as FISH, MLPA, or quantitative PCR can be employed. See Table 1, footnote 2.

If a deletion is not identified, KANSL1 sequence analysis is recommended.

Note: The deletion cannot be identified by routine chromosome analysis.

To evaluate at-risk relatives, targeted methods (FISH, MLPA, targeted [17q21.31 region-specific] CMA) or sequence analysis can be used to test for the 17q21.31 microdeletion or the KANSL1 sequence alteration, respectively.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion or mutation in the proband and/or of balanced carrier status in a parent (not reported to date).

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with deletion of the genes located within the 17q21.31 chromosome locus or with mutations in KANSL1.

Duplication of 17q21.31. Persons with a reciprocal duplication of the region deleted in the KANSL1-related intellectual disability syndrome differ phenotypically from those with the 17q21.31 microdeletion. The reciprocal duplication has been found in a girl with severe psychomotor developmental delay, microcephaly, facial dysmorphisms, abnormal digits, and hirsutism [Kirchhoff et al 2007] and in four individuals with mild psychomotor retardation and behavioral problems [Grisart et al 2009].

MAPT. Pathogenic gain-of-function mutations in the gene encoding microtubule-associated protein tau (MAPT) have been identified in individuals diagnosed with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) [Rademakers et al 2004]. These mutations result in pathologic deposits of hyperphosphorylated tau. This is in contrast to the haploinsufficiency of MAPT in the KANSL1-related intellectual disability syndrome. Therefore, there is no indication of an increased risk for FTDP-17 or related tauopathies in individuals who have the 17q21.31microdeletion.

Natural History

The KANSL1-related intellectual disability syndrome has a clinically recognizable phenotype that includes developmental delay/intellectual disability, neonatal/childhood hypotonia, dysmorphisms (Figure 1), congenital malformations and behavioral features (Table 2). Males and females are affected equally.

Global psychomotor developmental delay is noted in all individuals from an early age. The level of developmental delay varies significantly. The majority of individuals with the KANSL1-related intellectual disability syndrome function in the mild to moderate range of intellectual disability. Speech and language development seem to be particularly affected. Expressive language appears to be more severely affected than receptive language or motor skills.

Hypotonia with poor sucking and slow feeding can be evident in the neonatal period and during childhood. Feeding difficulties may require hospitalization and/or nasogastric tube feeding in some neonates.

Epilepsy including generalized seizures and unilateral clonic seizures is noted in 55%.

Growth. Short stature is not one of the most common clinical features of the syndrome. However, El Chehadeh-Djebbar et al reported on a child with a 17q21.31 microdeletion, short stature (-4 SD) and complete growth hormone deficiency and gonadotropic deficiency [El Chehadeh-Djebbar et al 2011]. Brain MRI showed partial pituitary stalk interruption, expanding the phenotypic spectrum of the syndrome.

Dysmorphic craniofacial features present in more than half of affected individuals include a broad forehead and/or high anterior hairline, long face, upward slanting palpebral fissures, epicanthic folds, a bulbous nose or tubular nose, large prominent ears, everted vermilion of the lower lip, and abnormal hair pigmentation and texture. The nose can have a high nasal bridge, a broad nasal root, long columella, and underdeveloped and/or thick alae nasi. The facial characteristics change with age. In infancy the facial gestalt is mostly characterized by hypotonia with an open mouth appearance. With increasing age there is usually elongation of the face and broadening of the chin, and the ‘‘tubular’’ or ‘‘pear’’ shape form of the nose may become more apparent.

Other common findings include dental anomalies, slender long fingers, persistence of the fetal fingertip pads, hypoplasia of the hand muscles, slender lower limbs, joint hypermobility, hip dislocation, and positional deformities of the feet. In addition, multiple nevi, other pigmentary skin abnormalities, and hair abnormalities have been reported [Koolen et al 2008, Tan et al 2009, Wright et al 2011].

Congenital heart defects are found in 39%. These are mainly septal heart defects, both atrial septal defects (ASD) and ventricular septal defects (VSD); however, cardiac valve disease, aortic root dilatation, and pulmonary stenosis have also been described.

Renal and urologic anomalies, including vesicoureteral reflux, hydronephrosis, pyelectasis, and duplex renal system, are found in 37%. Cryptorchidism has been reported in 71% of males.

Scoliosis is the most commonly observed spine anomaly; lordosis and kyphosis have also been reported and sometimes require surgery [Koolen et al 2008, Tan et al 2009].

Ophthalmologic abnormalities include strabismus and hypermetropia in 33%.

Behavior. In the vast majority of individuals, behavior is described as friendly, amiable, and cooperative, with or without frequent laughing. However, behavioral problems, including ADHD, have been reported [Koolen et al 2008, Tan et al 2009].

Life span. Longitudinal data are insufficient to determine life expectancy.

Genotype-Phenotype Correlations

Genotype-phenotype correlations in KANSL1-related intellectual disability syndrome have not been shown. Notably, the clinical features of children with the atypical deletions [Cooper et al 2011, Dubourg et al 2011, Kitsiou-Tzeli et al 2012, Koolen et al 2012b] and the mutations in KANSL1 [Koolen et al 2012b, Zollino et al 2012] are entirely in keeping with the phenotype seen in individuals with a classic 17q21.31 deletion.

Penetrance

Penetrance is 100%: clinical features of KANSL1-related intellectual disability syndrome are apparent in all individuals with the deletion or a KANSL1 mutation, although the extent and severity of clinical findings vary among individuals.

Nomenclature

The disorder was first recognized following microarray analysis among large cohorts of unselected individuals with intellectual disability [Koolen et al 2006, Sharp et al 2006, Shaw-Smith et al 2006]. The identification of individuals with a similar phenotype and a de novo KANSL1 mutation [Koolen et al 2012b, Zollino et al 2012] led OMIM to assign the name Koolen syndrome to the condition.

Prevalence

The estimated frequency of the KANSL1-related intellectual disability syndrome is approximately on the order of 0.64% (95% CI, 0.35%-0.93%) of individuals with unexplained intellectual disability, indicating that the KANSL1-related intellectual disability syndrome is currently greatly underdiagnosed in individuals with intellectual disability [Koolen et al 2008]. Based on these numbers, the prevalence of the KANSL1-related intellectual disability syndrome in the population as a whole is estimated at approximately one in 16,000 individuals [Koolen et al 2008].

However, the frequency of 0.64% may be too high. Analysis of 15,767 DNA samples from children with a general diagnosis of intellectual disability and/or developmental delay revealed 23 children with 17q21.31 microdeletions (0.2%) [Cooper et al 2011].

The KANSL1-related intellectual disability syndrome occurs with equal frequency in males and females [Koolen et al 2008].

The discovery that heterozygous mutations in KANSL1 are sufficient to cause the KANSL1-related intellectual disability syndrome phenotype is recent; thus, reliable figures on the prevalence of any KANSL1 mutations are not yet available.

Evaluations Following Initial Diagnosis

To establish the clinical consequences in an individual diagnosed with KANSL1-related intellectual disability syndrome, the following evaluations are recommended:

• Multidisciplinary developmental evaluation, including feeding assessment
• Comprehensive speech/language evaluation including audiologic examination
• A renal ultrasound examination
• Cardiac evaluation for possible heart anomalies including septal defect and aortic dilatation
• Brain imaging studies in individuals with microcephaly and/or seizures
• If seizures are suspected, EEG and consultation with a neurologist
• Consideration of a Chiari malformation type 1 in individuals with the KANSL1-related intellectual disability syndrome presenting suggestive symptoms (headache, neck pain, cerebellar signs or muscle weakness) [Terrone et al 2012]
• Investigation of growth hormone deficiency in individuals with KANSL1-related intellectual disability syndrome and short stature, defined by a height below - 2 SD scores for age and sex
• Involvement of a clinical geneticist following the initial diagnosis

Treatment of Manifestations

Treatment includes the following:

• Routine medical care by a pediatrician or other primary physician
• Early intervention with physiotherapy for feeding problems and motor delay related to hypotonia. Physical therapy aimed at strengthening the muscles as well as therapy to improve development of the child's fine and gross motor skills may also be beneficial.
• Speech therapy directed at improving verbal and nonverbal communication skills. Sign language, pictures, and computer touch screens may augment communication.
• Educational programming directed to the specific disabilities identified
• For epilepsy, treatment with routine antiepileptic drugs under the care of a neurologist. The seizures usually are easy to control with medication.
• Orthopedic care as required for scoliosis, hip dislocation, and positional deformities of the feet
• Standard treatment for cardiac, renal, urologic, and other medical issues
• Treatment for cryptorchidism if indicated

Surveillance

The following are appropriate:

• Ongoing pediatric care
• Specialized neurologic care for individuals with epilepsy
• Ophthalmologic examinations at routine intervals due to increased risk for hypermetropia and strabismus
• Monitoring for spine deformities
• Monitoring as needed of cardiac and renal/urologic abnormalities

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

The KANSL1-related intellectual disability syndrome, caused by a microdeletion at 17q21 or an intragenic KANSL1 mutation is inherited in an autosomal dominant manner, but almost all cases result from a de novo mutation.

Risk to Family Members

Parents of a proband

• To date, all cases resulting from a KANSL1 mutation have been de novo.
• To date, all microdeletions detected have been de novo, except for two families [Koolen et al 2012a]. The (phenotypically normal) mothers in both families were identified to have low-level somatic (and presumably gonadal) mosaicism [Koolen et al 2012a]. Thus, testing for mosaicism in the parents could be considered as a helpful tool in counseling, although gonadal mosaicism in one of the parents cannot be excluded.
• Balanced chromosome rearrangements in parents have not been reported.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the parents.
• When the parents are clinically unaffected, the risk to sibs is low (probably <1%) but greater than that of the general population because parents may have one of the following:
  • Germline mosaicism [Author, personal observation]
  • Low-level somatic mosaicism that also includes the germline [Koolen et al 2012a]
  • A balanced chromosomal rearrangement involving 17q21.31 (not reported but a possibility)

Offspring of a proband

• Individuals who have the 17q21.31 deletion or a KANSL1 mutation have a 50% chance of transmitting the deletion/mutation to each child.
• No individuals diagnosed with the KANSL1-related intellectual disability syndrome have been known to reproduce.

Other family members

• The risk to other family members depends on the status of the proband's parents.
• If a parent has a balanced chromosome rearrangement, his or her family members may be at risk.
• No parent with a balanced chromosome rearrangement has been reported to date.

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 parents of a child with the KANSL1-related intellectual disability syndrome.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing may be offered to unaffected parents who have had a child with a 17q21.31 microdeletion or a KANSL1 mutation.

Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed for 17q21.31 microdeletions using FISH, MLPA, or CMA in the manner described in Molecular Genetic Testing. Intragenic KANSL1 mutation can be identified using DNA sequence analysis of KANSL1 (see Molecular Genetic Testing).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for parents of a child with a 17q21.31microdeletion or a KANSL1 mutation. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Acknowledgments

The authors gratefully acknowledge the members of 17q21.31 microdeletion support groups (see chromo17europe.webs.com) and other parents for their participation in research and for their generous sharing of information.

Revision History

• 10 January 2013 (cd) Revision: sequence analysis of KANSL1 available clinically
• 20 November 2012 (me) Comprehensive update posted live
• 26 January 2010 (me) Review posted live
• 28 August 2009 (dak) Original submission