DiagnosisClinical 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 growthEpilepsyDysmorphic facial features (see Figure 1): Abnormal hair color/texture Broad forehead and/or high anterior hairline PtosisBlepharophimosisUpward slanting palpebral fissures Epicanthal folds Large/prominent earsBulbous nose or tubular noseEverted vermilion of the lower lip Heart anomaliesRenal/urologic anomaliesHypermobility of the jointsHypermetropiaDeformities of the feet and/or spine Friendly/amiable dispositionFigureFigure 1. Photographs of eight different individuals with a 17q21.31 deletion TestingCytogenetic 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with typical features of the KANSL1-related intellectual disability syndrome [Koolen et al 2012b, Zollino et al 2012, unpublished data].Clinical testingTable 1. Summary of Molecular Genetic Testing Used in KANSL1-Related Intellectual Disability Syndrome View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityKANSL1Deletion / duplication analysis 2, 3 ~600-kb deletion at 17q21.31 that includes KANSL1~95% 4ClinicalSequence analysisSequence variants 5~5% 4Genotyping 6Not applicableNot applicableResearch only1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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. 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 ~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]. Testing for the inversion is not routinely indicated (see Molecular Genetics).Interpretation of test resultsDeletion 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 KANSL1A 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).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 HistoryThe 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. Table 2. Features of KANSL1-Related Intellectual Disability SyndromeView in own windowFrequency ^{1FeaturesVery common (>75% of individuals)Distinctive facial features (see Clinical Diagnosis)Developmental delay/ intellectual disabilityHypotonia (childhood)Friendly/amiable dispositionCommon (50%-75%)EpilepsyMultiple nevi and other pigmentary skin and hair abnormalitiesNasal speechNarrow/high palateDental anomaliesSlender/long fingersJoint hypermobility and/or joint dislocation/dysplasiaStructural CNS anomaliesRenal & urogenital anomalies Less common (25%-50%)Heart defectsHypermetropiaStrabismusNarrow handsHypoplasia hand musclesHip dislocation/ dysplasiaPersistence of fingertip padsSlender lower limbsPositional deformity of the feetScoliosis/ kyphosisOccasional (10%-25%)Hearing loss due to chronic otitis mediaLow birth weightShort statureAbnormal head shape 2Pectus excavatumInfrequent (<10%)Cleft lip/palateMicrocephalyCataractPyloric stenosisFused vertebraeSpondylolisthesisHypothyroidism1. Koolen et al [2008], Tan et al [2009], www​.17q21.com2. Abnormal head shape may include craniosynostosisGlobal 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.}

Differential DiagnosisThe most common findings in the KANSL1-related intellectual disability syndrome, developmental delay and childhood hypotonia, are common and relatively nonspecific indications for molecular cytogenetic analysis. However, the concurrent finding of characteristic facial dysmorphic features, epilepsy, hypermetropia, congenital heart defects, renal or urologic anomalies, cryptorchidism, and/or friendly/amiable behavior may prompt specific consideration of the diagnosis of KANSL1-related intellectual disability syndrome. Other diagnoses that may be considered in affected individuals include:Deletion 22q11.2 (velocardiofacial syndrome) (VCFS). The KANSL1-related intellectual disability syndrome may be considered in patients who tested negative for deletion of 22q11.2. Developmental delay, long face, narrow palpebral fissures, prominent tubular nose, bulbous nasal tip, ventricular septal defects, and slender hands and digits are common clinical features in both syndromes.Prader-Willi syndrome (PWS). Clinical features of the KANSL1-related intellectual disability syndrome that may also be seen with PWS include intellectual disability, severe neonatal/childhood hypotonia, seizures, global developmental delay, strabismus, upslanting palpebral fissures, cryptorchidism, and blonde to light brown hair. However, in contrast to PWS, childhood hyperphagia and central obesity have not been reported in the KANSL1-related intellectual disability syndrome, and behavioral problems and sleep disturbances are less common.Fragile X syndrome. The face of adult males with the KANSL1-related intellectual disability syndrome may show some coarsening and elongation with increasing age, which may be similar to the facial gestalt of fragile X syndrome. The behavioral features, however, differ significantly. Angelman syndrome. Varela et al [2006] described a girl with a 17q21.31 microdeletion and suggested a phenotypic resemblance to Angelman syndrome.Cardiofaciocutaneous syndrome (CFC). Wright et al described four individuals with 17q21.31 microdeletions where previously the diagnosis of CFC syndrome was suggested [Wright et al 2011]. These individuals have a large number of nevi and other pigmentary skin abnormalities. These features, together with a coarse facial appearance, relative macrocephaly and significant learning disabilities, had led to the previous diagnostic suggestion of CFC syndrome in each of the four individuals.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations 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 assessmentComprehensive speech/language evaluation including audiologic examinationA renal ultrasound examinationCardiac evaluation for possible heart anomalies including septal defect and aortic dilatationBrain imaging studies in individuals with microcephaly and/or seizuresIf seizures are suspected, EEG and consultation with a neurologistConsideration 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 sexInvolvement of a clinical geneticist following the initial diagnosis Treatment of ManifestationsTreatment includes the following:Routine medical care by a pediatrician or other primary physicianEarly 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 feetStandard treatment for cardiac, renal, urologic, and other medical issuesTreatment for cryptorchidism if indicatedSurveillanceThe following are appropriate:Ongoing pediatric careSpecialized neurologic care for individuals with epilepsyOphthalmologic examinations at routine intervals due to increased risk for hypermetropia and strabismus Monitoring for spine deformities Monitoring as needed of cardiac and renal/urologic abnormalitiesEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. KANSL1-Related Intellectual Disability Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNot applicable17q21​.31Not applicable KANSL117q21​.31KAT8 regulatory NSL complex subunit 1KANSL1 @ LOVDKANSL1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for KANSL1-Related Intellectual Disability Syndrome (View All in OMIM) View in own window 610443KOOLEN-DE VRIES SYNDROME; KDVS 612452KAT8 REGULATORY NSL COMPLEX SUBUNIT 1; KANSL117q21.31 Microdeletion Normal allelic variants. Within the Genome Reference Consortium Human genome build 37 (GRCh37) reference assembly, the 17q21.31 locus involved is defined approximately by chr17:43.4–44.8 Mbp. The locus encompasses ~600 kb of unique sequence and is flanked by extensive low-copy repeats (LCRs). Two haplotypes exist, in direct (H1) and inverted (H2) orientation [Stefansson et al 2005]. The H2 haplotype is enriched in Europeans, and carriers are predisposed to the 17q21.31 microdeletion [Koolen et al 2006, Sharp et al 2006, Koolen et al 2008, Zody et al 2008]. In every parent-child trio tested to date, the parent originating the deleted chromosome 17 carries at least one chromosome with H2 haplotype, which is significantly different from the approximately 20% frequency of the inversion in the European population reported by Stefansson et al (p<10^-5, Pearson’s Chi square test) [Stefansson et al 2005, Koolen et al 2008]. The H2 haplotype results in a genomic structure with directly oriented LCR subunits that can undergo a deletion rearrangement via NAHR [Lupski 1998], suggesting that the inversion found in all parents of origin may be a necessary factor for the deletion to occur [Lupski 2006]. In the general population the H2 inversion is a risk factor for having offspring with a 17q21.31 microdeletion [Koolen et al 2008]. However, the frequency of de novo 17q21.31 microdeletions in carriers of the H2 inversion is low, and other as-yet poorly understood factors are likely to be important in the generation of the deletion.Pathologic allelic variants. The breakpoints of the 17q21.31 microdeletion were resolved with high through-put (next-generation sequencing) [Itsara et al 2012]. For two cases, breakpoints consistent with nonallelic homologous recombination involving only H2 chromosomal haplotypes, were observed. Molecular resolution revealed that the breakpoints occurred at different locations within a 145 kb LCR and disrupted KANSL1. In a third case, unequal crossover occurred interchromosomally between the H1 and H2 haplotypes and also this event was mediated by a homologous sequence [Itsara et al 2012].Besides the recurrent classic 17q21.31 microdeletion, several atypical 17q21.31 deletions have been described in children with clinical features typically associated with the classic 17q21.31 microdeletion [Cooper et al 2011, Dubourg et al 2011, Kitsiou-Tzeli et al 2012, Koolen et al 2012b]. All these atypical deletions encompass at least KANSL1. Moreover, de novo mutations were identified in children with clinical features that are in keeping with the phenotype seen in individuals with a classic17q21.31 deletion, showing that KANSL1 is actually the gene involved in this microdeletion syndrome [Koolen et al 2012b, Zollino et al 2012].KANSL1Normal allelic variants. There are several transcript variants of KANSL1 (Table A). The longest, NM_001193466.1, has 15 exons.Pathologic allelic variants. To date, de novo KANSL1 mutations have been identified in at least six children with typical features of the KANSL1-related intellectual disability syndrome [Koolen et al 2012b, Zollino et al 2012, unpublished data]. All mutations result in or predict haploinsufficiency of KANSL1. Table 3. Selected KANSL1 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.916C>Tp.Gln306XNM_001193466​.1
NP_001180395​.1c.1816C>Tp.Arg606Xc.1652+1G>ASee footnote 1c.2785_2786delAGp.Arg929Glyfs*44c.1867_1870delp.Ile623Alafs*6c.985_986delp.Leu329Glufs*22See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Splice-site mutation resulting in skipping of exon 6, causing a frameshift and premature termination of the KANSL1 mRNA [Koolen et al 2012b]Normal gene product. The longer KAT8 regulatory NSL complex subunit 1 isoform, NP_001180395.1, has 1105 amino acids. KANSL1 is a widely expressed gene encoding a member of the highly conserved nonspecific lethal (NSL) complex [Mendjan et al 2006]. This complex contains, among other proteins, the K (lysine) acetyltransferase KAT8, which influences gene expression through acetylation of histone H4K16 and the transcription factor p53 [Li et al 2009]. The NSL complex is recruited to target genes to facilitate activation of transcription in coordination with the histone H2K4 methyltransferase, MLL [Dou et al 2005]. Abnormal gene product. Interestingly, using whole transcriptome RNA-Seq, it was shown that genes that are differentially expressed in EBV-transformed cell lines from individuals with KANSL1-related intellectual disability syndrome and in those from controls are enriched in neuronal/synaptic processes, which is in line with the clinical phenotype [Koolen et al 2012b].