Clinical characteristics.

Koolen-de Vries syndrome (KdVS) is characterized by developmental delay / intellectual disability, neonatal/childhood hypotonia, dysmorphisms, congenital malformations, and behavioral features. Psychomotor developmental delay is noted in all individuals from an early age. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability. Other findings include speech and language delay (100%), epilepsy (~33%), congenital heart defects (25%-50%), renal and urologic anomalies (25%-50%), and cryptorchidism (71% of males). Behavior in most is described as friendly, amiable, and cooperative.

Diagnosis/testing.

The diagnosis of Koolen-de Vries syndrome is established in a proband who has either a heterozygous 500- to 650-kb deletion at chromosome 17q21.31 that includes KANSL1 or a heterozygous intragenic pathogenic variant in KANSL1. Note: The 17q21.31 deletion cannot be identified by analysis of G-banded chromosomes or other cytogenetic banding techniques.

Management.

Treatment of manifestations: Physiotherapy for gross and fine motor delays; speech therapy to support early feeding challenges and communication development; educational programs directed to specific disabilities identified. Routine treatment of: vision issues / strabismus; hearing loss; cardiac, renal, and urologic problems; epilepsy; scoliosis, hip dislocation, and positional deformities of the feet; multiple nevi.

Surveillance: Routine ophthalmologic examinations for hypermetropia and strabismus; monitoring for progressive spine deformities; routine monitoring for other medication complications depending on the organ system involved.

Genetic counseling.

Koolen-de Vries syndrome, caused by a deletion at 17q21.31 or a pathogenic variant in KANSL1, is inherited in an autosomal dominant manner; to date almost all cases result from a de novo deletion or KANSL1 pathogenic variant. Thus, most affected individuals represent simplex cases (i.e., a single occurrence in a family). The recurrence risk for future pregnancies is low (probably <1%) but greater than that of the general population because of the possibility of germline mosaicism in one of the parents. Prenatal testing is technically feasible, but the likelihood of recurrence in families who have had an affected child is low.

Suggestive Findings

Koolen-de Vries syndrome (KdVS) should be suspected in individuals presenting with mild-to-moderate developmental delay or intellectual disability in which speech and language development is particularly affected, in combination with additional clinical findings.

Additional clinical findings

• Neonatal/childhood hypotonia and feeding difficulties
• Epilepsy
• Dysmorphic facial features (see Clinical Description and Figure 1)
• Hypermetropia
• Congenital heart anomalies
• Congenital renal/urologic anomalies
• Hypermobility of the joints and/or joint dislocation/dysplasia
• Deformities of the spine and/or feet

Figure 1.

Photographs of eight individuals with a 17q21.31 deletion

Establishing the Diagnosis

The diagnosis of Koolen-de Vries syndrome is established in a proband with typical clinical findings and detection of any of the following (see Table 1):

• A heterozygous deletion at chromosome 17q21.31 that includes KANSL1 (~95% of affected individuals) [Koolen et al 2006, Sharp et al 2006, Shaw-Smith et al 2006]. The 17q21.31 deletion is typically 500- to 650-kb in size (hg19: chr17:43,700,000-44,250,000) and is flanked by segmental duplications.
• A heterozygous intragenic pathogenic variant in KANSL1 (~5% of affected individuals) [Koolen et al 2012b, Zollino et al 2012, Zollino et al 2015, Koolen et al 2016].
• Haploinsufficiency of KANSL1 due to chromosome rearrangements [Moreno-Igoa et al 2015].

Molecular genetic testing approaches can include a combination of chromosomal microarray (CMA), single-gene testing, a multigene panel, and comprehensive genomic testing (exome sequencing, exome array, genome sequencing).

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including KANSL1) that cannot be detected by sequence analysis. CMA is recommended first because deletions are identified in ~95% of probands (see Table 1). The ability to determine the size of the deletion depends on the type of microarray used and the density of probes in the 17q21.31 region.

If chromosomal microarray does not identify the cause of the individual’s features, gene-targeted testing, which requires that the clinician to determine which gene(s) are likely involved, or genomic testing may be considered. Because the phenotype of KdVS is broad, individuals with the distinctive findings described in Suggestive Findings may be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of KdVS has not been considered are more likely to be diagnosed using other genomic testing (see Option 2).

Clinical Description

Koolen-de Vries syndrome (KdVS) has a clinically recognizable phenotype that includes neonatal/childhood hypotonia, developmental delay / intellectual disability, dysmorphisms (Figure 1), speech and language delays, congenital malformations, and behavioral features (Table 2). Males and females are affected equally.

Dysmorphic craniofacial features that may suggest KdVS:

• Upslanted palpebral fissure
• Blepharophimosis
• Epicanthus
• Ptosis
• Pear-shaped nose
• Bulbous nose
• Large/protruding ears

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.

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. Beyond infancy and into the preschool years, many children experience problems chewing difficult, lumpy, or solid textures [Morgan et al 2018a].

Psychomotor developmental delay is noted in all individuals from an early age. The level of developmental delay varies significantly. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability.

• Communication disorder is a core feature of KdVS with a common speech and language phenotype seen. This includes an overriding "double hit" of oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development [Morgan et al 2018a].
  • First words occur between ages 2.5 and 3.5 years on average.
  • Childhood apraxia of speech (CAS) is common in these preschool years, and speech development is effortful even when supported with intensive therapy.
  • Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
  • Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
• Stuttering is present in a handful of cases (17%), and has been noted in adolescence only.
• Receptive and expressive language abilities are typically commensurate (79%), both being severely affected relative to peers.
• Children are reported as sociable with a desire to communicate; in some individuals (36%) social skill impairments appear with increasing age and increasing social demands.

Epilepsy, including generalized seizures and unilateral clonic seizures, is noted in approximately 33% of affected individuals. The epilepsy phenotypic spectrum in KdVS is broad; however, most individuals have focal seizures, with some having a phenotype resembling the self-limited focal epilepsies of childhood [Myers et al 2017].

• The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features.
• Multifocal epileptiform discharges are the typical EEG pattern.
• Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance (see Table 2).

Other common findings (see Table 2) 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 [Wright et al 2011, Zollino et al 2015, Koolen et al 2016].

• Congenital heart defects mainly include septal heart defects; however, cardiac valve disease, aortic root dilatation, and pulmonary stenosis have also been described.
• Renal and urologic anomalies include vesicoureteral reflux, hydronephrosis, pyelectasis, and duplex renal system. Cryptorchidism has been reported in the majority 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].
• Behavior. In the vast majority of individuals, behavior is described as friendly, amiable, and cooperative, with or without frequent laughing. However, behavior problems, including attention-deficit/hyperactivity disorder, have been reported [Koolen et al 2008, Tan et al 2009, Koolen et al 2016].

Growth. Short stature is not one of the most common clinical features of the syndrome. However, El Chehadeh-Djebbar et al [2011] reported on a child with a 17q21.31 deletion, short stature (-4 SD), 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.

Life span. Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is typical.

Genotype-Phenotype Correlations

Genotype-phenotype correlations in KdVS have not been shown. Notably, the clinical features of affected individuals with atypical deletions and those with pathogenic variants in KANSL1 are in keeping with the phenotype seen in individuals with a classic 17q21.31 deletion [Zollino et al 2015, Koolen et al 2016].

Penetrance

Penetrance is 100%: clinical features of KdVS are apparent in all individuals with a deletion of or a pathogenic variant in KANSL1, 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 pathogenic variant [Koolen et al 2012b, Zollino et al 2012] led OMIM to assign the name "Koolen-de Vries syndrome" to the condition.

Prevalence

The prevalence of Koolen-de Vries syndrome is unknown. The authors estimate the prevalence of the 17q21.31 deletion at 1:55,000 individuals [Koolen et al 2016]. The prevalence of individuals with a pathogenic sequence variant in KANSL1 cannot be determined with precision owing to the limited number of such affected individuals identified thus far. Preliminary data suggest that pathogenic KANSL1 sequence variants may be as frequent as deletions, but more studies are needed to determine an unbiased prevalence.

Koolen-de Vries syndrome occurs with equal frequency in males and females [Koolen et al 2008].

Evaluations Following Initial Diagnosis

To establish the clinical consequences in an individual diagnosed with Koolen-de Vries syndrome (KdVS), the following evaluations are recommended if they have not already been completed.

Treatment of Manifestations

Treatment includes routine medical care by a pediatrician or other primary physician and the following.

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.

Surveillance

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 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

Koolen-de Vries syndrome (KdVS), caused by a heterozygous deletion at 17q21.31 or a heterozygous intragenic KANSL1 pathogenic variant, is inherited in an autosomal dominant manner. Almost all affected individuals represent simplex cases (i.e., a single affected individual in the family).

Risk to Family Members

Parents of a proband

• To date, all reported intragenic KANSL1 pathogenic variants and almost all reported 17q21.31 deletions have been de novo in the proband.
• Evaluation of the parents by testing that will detect the 17q21.31 deletion or intragenic KANSL1 pathogenic variant present in the proband is recommended. FISH analysis in the parents to evaluate for a balanced insertion and/or translocations may also be considered. Note: Testing for the 17q21.31 inversion polymorphism is not recommended (see Molecular Genetics).
• If the 17q21.31 deletion or intragenic KANSL1 pathogenic variant cannot be identified in the leukocyte DNA of either parent, the most likely explanation is that the genetic alteration is de novo in the proband. Another possible explanation is germline and/or somatic and germline mosaicism in a parent. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [Koolen et al 2012a].
• Theoretically, a parent could have a balanced chromosome rearrangement involving 17q21.31 resulting in a 17q21.31 deletion in an affected child; balanced chromosome rearrangements in parents involving 17q21.31 have not been reported to date.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If the parents are clinically unaffected, the risk to sibs is low (probably <1%) but greater than that of the general population because the parents may have one of the following:
  • Germline mosaicism [Koolen et al 2012a]
  • A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible)

Offspring of a proband

• Individuals who have the 17q21.31 deletion or a KANSL1 pathogenic variant have a 50% chance of transmitting the genetic alteration to each child.
• To date, one individual diagnosed with KdVS has been known to reproduce [Author, personal observation].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a KdVS-related genetic alteration or, theoretically, a balanced chromosomal rearrangement, his or her family members may be at risk.

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 KdVS.

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

Molecular genetic testing. Once the KdVS-related genetic alteration has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

17q21.31 Deletion

The 17q21.31 deletion is typically 500 to 650 kb in size (hg19: chr17:43,700,000-44,250,000) and is flanked by segmental duplications that mediate nonallelic homologous recombination [Itsara et al 2012]. Genetic testing of the 17q21.31 genomic region is challenging. The mapping and interpretation of the deletion breakpoints are confounded by the structural complexity and genomic variation of the 17q21.31 locus [Koolen et al 2016]. 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]. 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.

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 pathogenic variants were identified in children with clinical features that are in keeping with the phenotype seen in individuals with a classic 17q21.31 deletion, showing that KANSL1 is actually the gene involved in this microdeletion syndrome [Koolen et al 2012b, Zollino et al 2012].

KANSL1

Gene structure.KANSL1 has several transcript variants. The longest, NM_001193466.1, has 15 exons. For a detailed summary of gene, transcript, and protein information see Table A, Gene.

Pathogenic variants. To date, all pathogenic KANSL1 variants reported are truncating variants. [Koolen et al 2012b, Zollino et al 2012, Zollino et al 2015, Koolen et al 2016].

The 17q21.31 inversion polymorphism (H2 haplotype) and the copy number polymorphism clusters encompassing exons 1–3 of KANSL1 contribute to difficulties in SNV calling, such as loss-of-function variant "artefacts" in KANSL1 [Koolen et al 2016]. The detection of a truncating variant in exons 1-3 of KANSL1 is not sufficient to make a diagnosis of KdVS. In these cases, next to a compatible clinical phenotype, variant analysis of the parental samples is of the utmost importance to verify that the possibly pathogenic variant occurred de novo.

Normal gene product.KANSL1 encodes KAT8 regulatory NSL complex subunit 1, the longer isoform of which (NP_001180395.1) has 1,105 amino acids. KANSL1 is a scaffold protein of the nonspecific lethal complex that contains the histone acetyltransferase MOF, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation [Mendjan et al 2006].

H4K16ac activates the expression of a broad set of genes including several autophagy-related genes [Füllgrabe et al 2013]. Autophagy is a catabolic process important for the clearance of protein aggregates and damaged organelles within the cell, which is essential for cell homeostasis and survival. Autophagy is essential in neurons, not only for cell homeostasis but also for regulation of development and function [Shehata et al 2012, Tang et al 2014].

Abnormal gene product. Studies in mice have shown that heterozygous loss of Kansl1 leads to changes in gene expression related to synaptic transmission and to a decrease in basal synaptic transmission and plasticity [Arbogast et al 2017], but the underlying cellular mechanisms remain unknown. H4K16ac is known to be essential for the regulation of autophagy, a process controlling degradation and recycling of proteins and shown to play a role in synapse development and function. Disruption in autophagy can therefore lead to impairments in neuronal development and synaptic transmission and could play an essential role in the pathophysiology of KdVS.

Literature Cited

• Arbogast T, Iacono G, Chevalier C, Afinowi NO, Houbaert X, van Eede MC, Laliberte C, Birling MC, Linda K, Meziane H, Selloum M, Sorg T, Nadif Kasri N, Koolen DA, Stunnenberg HG, Henkelman RM, Kopanitsa M, Humeau Y, De Vries BBA, Herault Y. Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition. PLoS Genet. 2017;13:e1006886. [PMC free article: PMC5531616] [PubMed: 28704368]
• Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, Abdel-Hamid H, Bader P, McCracken E, Niyazov D, Leppig K, Thiese H, Hummel M, Alexander N, Gorski J, Kussmann J, Shashi V, Johnson K, Rehder C, Ballif BC, Shaffer LG, Eichler EE. A copy number variation morbidity map of developmental delay. Nat Genet. 2011;43:838–46. [PMC free article: PMC3171215] [PubMed: 21841781]
• Dubourg C, Sanlaville D, Doco-Fenzy M, Le Caignec C, Missirian C, Jaillard S, Schluth-Bolard C, Landais E, Boute O, Philip N, Toutain A, David A, Edery P, Moncla A, Martin-Coignard D, Vincent-Delorme C, Mortemousque I, Duban-Bedu B, Drunat S, Beri M, Mosser J, Odent S, David V, Andrieux J. Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation. Eur J Med Genet. 2011;54:144–51. [PubMed: 21094706]
• El Chehadeh-Djebbar S, Callier P, Masurel-Paulet A, Bensignor C, Méjean N, Payet M, Ragon C, Durand C, Marle N, Mosca-Boidron AL, Huet F, Mugneret F, Faivre L, Thauvin-Robinet C. 17q21.31 microdeletion in a patient with pituitary stalk interruption syndrome. Eur J Med Genet. 2011;54:369–73. [PubMed: 21397059]
• Füllgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q, Hermanson O, Rosenfeld MG, Klionsky DJ, Joseph B. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Autophagy. 2013;9:1621–3. [PMC free article: PMC4006103] [PubMed: 23863932]
• Grieco JC, Bahr RH, Schoenberg MR, Conover L, Mackie LN, Weeber EJ. Quantitative measurement of communication ability in children with Angelman syndrome. J Appl Res Intellect Disabil. 2018;31:e49–e58. [PubMed: 27990716]
• Grisart B, Willatt L, Destrée A, Fryns JP, Rack K, de Ravel T, Rosenfeld J, Vermeesch JR, Verellen-Dumoulin C, Sandford R. 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction. J Med Genet. 2009;46:524–30. [PubMed: 19502243]
• Itsara A, Vissers LE, Steinberg KM, Meyer KJ, Zody MC, Koolen DA, de Ligt J, Cuppen E, Baker C, Lee C, Graves TA, Wilson RK, Jenkins RB, Veltman JA, Eichler EE. Resolving the breakpoints of the 17q21.31 microdeletion syndrome with next-generation sequencing. Am J Hum Genet. 2012;90:599–613. [PMC free article: PMC3322237] [PubMed: 22482802]
• Kirchhoff M, Bisgaard AM, Duno M, Hansen FJ, Schwartz M. A. 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. Eur J Med Genet. 2007;50:256–63. [PubMed: 17576104]
• Kitsiou-Tzeli S, Frysira H, Giannikou K, Syrmou A, Kosma K, Kakourou G, Leze E, Sofocleous C, Kanavakis E, Tzetis M. Microdeletion and microduplication 17q21.31 plus an additional CNV, in patients with intellectual disability, identified by array-CGH. Gene. 2012;492:319–24. [PubMed: 22037486]
• Koolen DA, Dupont J, de Leeuw N, Vissers LE, van den Heuvel SP, Bradbury A, Steer J, de Brouwer AP, Ten Kate LP, Nillesen WM, de Vries BB, Parker MJ. Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism. Eur J Hum Genet. 2012a;20:729–33. [PMC free article: PMC3376266] [PubMed: 22293690]
• Koolen DA, Kramer JM, Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, Toutain A, Amiel J, Malan V, Tsai AC, Cheung SW, Gilissen C, Verwiel ET, Martens S, Feuth T, Bongers EM, de Vries P, Scheffer H, Vissers LE, de Brouwer AP, Brunner HG, Veltman JA, Schenck A, Yntema HG, de Vries BB. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012b;44:639–41. [PubMed: 22544363]
• Koolen DA, Pfundt R, Linda K, Beunders G, Veenstra-Knol HE, Conta JH, Fortuna AM, Gillessen-Kaesbach G, Dugan S, Halbach S, Abdul-Rahman OA, Winesett HM, Chung WK, Dalton M, Dimova PS, Mattina T, Prescott K, Zhang HZ, Saal HM, Hehir-Kwa JY, Willemsen MH, Ockeloen CW, Jongmans MC, Van der Aa N, Failla P, Barone C, Avola E, Brooks AS, Kant SG, Gerkes EH, Firth HV, Õunap K, Bird LM, Masser-Frye D, Friedman JR, Sokunbi MA, Dixit A, Splitt M, Study DDD, Kukolich MK, McGaughran J, Coe BP, Flórez J, Nadif Kasri N, Brunner HG, Thompson EM, Gecz J, Romano C, Eichler EE, de Vries BB. The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant. Eur J Hum Genet. 2016;24:652–9. [PMC free article: PMC4930086] [PubMed: 26306646]
• Koolen DA, Sharp AJ, Hurst JA, Firth HV, Knight SJ, Goldenberg A, Saugier-Veber P, Pfundt R, Vissers LE, Destrée A, Grisart B, Rooms L, Van der Aa N, Field M, Hackett A, Bell K, Nowaczyk MJ, Mancini GM, Poddighe PJ, Schwartz CE, Rossi E, De Gregori M, Antonacci-Fulton LL, McLellan MD 2nd, Garrett JM, Wiechert MA, Miner TL, Crosby S, Ciccone R, Willatt L, Rauch A, Zenker M, Aradhya S, Manning MA, Strom TM, Wagenstaller J, Krepischi-Santos AC, Vianna-Morgante AM, Rosenberg C, Price SM, Stewart H, Shaw-Smith C, Brunner HG, Wilkie AO, Veltman JA, Zuffardi O, Eichler EE, de Vries BB. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet. 2008;45:710–20. [PMC free article: PMC3071570] [PubMed: 18628315]
• Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, Kooy RF, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, van Kessel AG, Sistermans EA, Veltman JA, Brunner HG, de Vries BB. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet. 2006;38:999–1001. [PubMed: 16906164]
• Mendjan S, Taipale M, Kind J, Holz H, Gebhardt P, Schelder M, Vermeulen M, Buscaino A, Duncan K, Mueller J, Wilm M, Stunnenberg HG, Saumweber H, Akhtar A. Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. Mol Cell. 2006;21:811–23. [PubMed: 16543150]
• Moreno-Igoa M, Hernández-Charro B, Bengoa-Alonso A, Pérez-Juana-del-Casal A, Romero-Ibarra C, Nieva-Echebarria B, Ramos-Arroyo MA. KANSL1 gene disruption associated with the full clinical spectrum of 17q21.31 microdeletion syndrome. BMC Med Genet. 2015;16:68. [PMC free article: PMC4593202] [PubMed: 26293599]
• Morgan AT, Haaften LV, van Hulst K, Edley C, Mei C, Tan TY, Amor D, Fisher SE, Koolen DA. Early speech development in Koolen de Vries syndrome limited by oral praxis and hypotonia. Eur J Hum Genet. 2018a;26:75–84. [PMC free article: PMC5839037] [PubMed: 29225339]
• Morgan AT, Murray E, Liégeois FJ. Interventions for childhood apraxia of speech. Cochrane Database Syst Rev. 2018b;5:CD006278. [PMC free article: PMC6494637] [PubMed: 29845607]
• Myers KA, Mandelstam SA, Ramantani G, Rushing EJ, de Vries BB, Koolen DA, Scheffer IE. The epileptology of Koolen-de Vries syndrome: electro-clinico-radiologic findings in 31 patients. Epilepsia. 2017;58:1085–94. [PubMed: 28440867]
• Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, Stewart H, Price SM, Blair E, Hennekam RC, Fitzpatrick CA, Segraves R, Richmond TA, Guiver C, Albertson DG, Pinkel D, Eis PS, Schwartz S, Knight SJ, Eichler EE. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet. 2006;38:1038–42. [PubMed: 16906162]
• Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, Curley R, Cumming S, Dunn C, Kalaitzopoulos D, Porter K, Prigmore E, Krepischi-Santos AC, Varela MC, Koiffmann CP, Lees AJ, Rosenberg C, Firth HV, de Silva R, Carter NP. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet. 2006;38:1032–7. [PubMed: 16906163]
• Shehata M, Matsumura H, Okubo-Suzuki R, Ohkawa N, Inokuchi K. Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J Neurosci. 2012;32:10413–22. [PMC free article: PMC6703735] [PubMed: 22836274]
• Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J, Baker A, Jonasdottir A, Ingason A, Gudnadottir VG, Desnica N, Hicks A, Gylfason A, Gudbjartsson DF, Jonsdottir GM, Sainz J, Agnarsson K, Birgisdottir B, Ghosh S, Olafsdottir A, Cazier JB, Kristjansson K, Frigge ML, Thorgeirsson TE, Gulcher JR, Kong A, Stefansson K. A common inversion under selection in Europeans. Nat Genet. 2005;37:129–37. [PubMed: 15654335]
• Tan TY, Aftimos S, Worgan L, Susman R, Wilson M, Ghedia S, Kirk EP, Love D, Ronan A, Darmanian A, Slavotinek A, Hogue J, Moeschler JB, Ozmore J, Widmer R, Bruno D, Savarirayan R, Peters G. Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome. J Med Genet. 2009;46:480–9. [PubMed: 19447831]
• Tang P, Hou H, Zhang L, Lan X, Mao Z, Liu D, He C, Du H, Zhang L. Autophagy reduces neuronal damage and promotes locomotor recovery via inhibition of apoptosis after spinal cord injury in rats. Mol Neurobiol. 2014;49:276–87. [PubMed: 23954967]
• Terrone G, D'Amico A, Imperati F, Carella M, Palumbo O, Gentile M, Canani RB, Melis D, Romano A, Parente I, Riccitelli M, Del Giudice E. A further contribution to the delineation of the 17q21.31 microdeletion syndrome: central nervous involvement in two Italian patients. Eur J Med Genet. 2012;55:466–71. [PubMed: 22659270]
• Wright EB, Donnai D, Johnson D, Clayton-Smith J. Cutaneous features in 17q21.31 deletion syndrome: a differential diagnosis for cardio-facio-cutaneous syndrome. Clin Dysmorphol. 2011;20:15–20. [PMC free article: PMC3000393] [PubMed: 21084979]
• Zody MC, Jiang Z, Fung HC, Antonacci F, Hillier LW, Cardone MF, Graves TA, Kidd JM, Cheng Z, Abouelleil A, Chen L, Wallis J, Glasscock J, Wilson RK, Reily AD, Duckworth J, Ventura M, Hardy J, Warren WC, Eichler EE. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat Genet. 2008;40:1076–83. [PMC free article: PMC2684794] [PubMed: 19165922]
• Zollino M, Orteschi D, Murdolo M, Lattante S, Battaglia D, Stefanini C, Mercuri E, Chiurazzi P, Neri G, Marangi G. Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. Nat Genet. 2012;44:636–8. [PubMed: 22544367]
• Zollino M, Marangi G, Ponzi E, Orteschi D, Ricciardi S, Lattante S, Murdolo M, Battaglia D, Contaldo I, Mercuri E, Stefanini MC, Caumes R, Edery P, Rossi M, Piccione M, Corsello G, Della Monica M, Scarano F, Priolo M, Gentile M, Zampino G, Vijzelaar R, Abdulrahman O, Rauch A, Oneda B, Deardorff MA, Saitta SC, Falk MJ, Dubbs H, Zackai E. Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients. J Med Genet. 2015;52:804–14. [PubMed: 26424144]

Author Notes

Radboudumc Center of Expertise Rare Congenital Developmental Disorders Website

Acknowledgments

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

Revision History

• 13 June 2019 (ma) Comprehensive update posted live
• 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