Clinical Diagnosis

The clinical spectrum of the 17q21.31 microdeletion syndrome is variable. Besides developmental delay and intellectual disability, no single clinical feature is required to establish the diagnosis.

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

• Delayed speech

• Mild to moderate hypotonia

• Normal growth

• Epilepsy

• Dysmorphic facial features (see Figure 1):

  • Abnormal hair color/texture

  • High/broad forehead

  • Ptosis

  • Blepharophimosis

  • Upward slanting palpebral fissures

  • Epicanthal folds

  • Large/prominent ears

  • Tubular or pear-shaped nose

  • Bulbous nasal tip

  • Everted 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 deletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Molecular Genetic Testing

Critical region. The diagnosis of the 17q21.31 microdeletion syndrome is confirmed by demonstration of a 500- to 650-kb heterozygous deletion at chromosome 17q21.31 [Koolen et al 2006, Sharp et al 2006, Shaw-Smith et al 2006]. The minimal critical region that is recurrently deleted in patients but not in controls is 424 kb (41.046.729-41.470.954 Mb, hg17; see NCBI MapViewer) [Koolen et al 2008].

Clinical testing

Deletion/duplication analysis. The 17q21.31 microdeletion can be detected by any molecular method that determines the copy number of genomic sequences within the deleted region. Both whole-genome or targeted approaches can be applied.

• Genomic microarray technologies. Array genomic hybridization (aGH) BAC or oligonucleotide arrays or genotyping arrays can detect the common deletion in a proband. The ability to determine the size of the deletion accurately depends on the type of microarray used and the density of probes in the q21.31 region.

• Targeted deletion analysis. Targeted methods such as fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) can be used if the syndrome is suspected clinically or for the 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.
  
  Whether or not it is possible to determine the size of the deletion depends on the number and distribution of probes tested in the q21.31 region. The size of a deletion cannot be determined with a single FISH probe.

Research testing

Genotyping. All unaffected parents originating the deleted chromosome 17 who have been tested so far have 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 the parents for the H2 lineage is available on a research basis only. Testing for the inversion is not routinely indicated.

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.

Table 1. Summary of Molecular Genetic Testing Used in 17q21.31 Microdeletion Syndrome

View in own window

Chromosomal Region	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
17q21.31	Deletion/duplication analysis 2	Deletion of 500 kb - 650 kb in size	100%	Clinical

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 genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted aGH (gene/segment-specific) may be used. A full aGH analysis that detects deletions/duplications across the genome may also include this gene/segment. See aGH.

Interpretation of test results. 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 targets show an abnormal copy number by chance.

Testing Strategy

To establish the diagnosis in a proband requires detection of a 17q21.31 microdeletion that includes the 424-kb minimal critical region.

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

If the 17q21.31 microdeletion syndrome is suspected based on clinical features, a targeted technique can be employed, such as FISH or MLPA analysis.

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

To evaluate at-risk relatives, targeted methods such as FISH, MLPA, or (region-specific) aGH can be used to test for the 17q21.31 deletion.

For the estimation of the recurrence risk, additional testing of the parents by FISH could be considered, as it can detect balanced rearrangements involving 17q21.31 (but not the polymorphic H2 inversion) in phenotypically normal carriers. Parents with balanced rearrangements have not yet been reported, nor have offspring of individuals with a 17q21.31 deletion.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion in the proband and/or of balanced carrier status in a parent.

Genetically Related (Allelic) Disorders

Pathogenic gain-of-function mutations in the gene encoding microtubule-associated protein tau (MAPT) have been identified in people 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 17q21.31 deletion syndrome. Therefore, there is no indication of an increased risk for FTDP-17 or related tauopathies in individuals who have the 17q21.31 deletion.

For the other genes in the deleted region, no pathogenic mutations have been reported in man.

Persons with a reciprocal duplication of the region deleted in the 17q21.31 microdeletion 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].

Natural History

The 17q21.31 microdeletion syndrome has a clinically recognizable phenotype that includes developmental delay/intellectual disability, 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 17q21.31 microdeletion syndrome function in the mild to moderate range of intellectual disability. Speech and language development seem to be particularly affected.

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%.

Dysmorphic craniofacial features present in more than half of the individuals include a high/broad forehead, long face, upward slanting palpebral fissures, epicanthic folds, an abnormally formed nose (either ‘‘tubular’’ or ‘‘pear’’ shaped), bulbous nasal tip, large prominent ears, everted lower lip, and abnormal hair pigmentation and texture. The nose can have a high nasal bridge, a broad nasal root, long columella, and hypoplastic 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. However, 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 becomes 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.

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.

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.

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

Genotype-Phenotype Correlations

Genotype-phenotype correlations in 17q21.31 microdeletion syndrome have not been shown.

Penetrance

Penetrance is 100%: clinical features of 17q21.31 microdeletion syndrome are apparent in all individuals with the deletion, although the extent and severity of clinical findings vary between individuals.

Prevalence

The frequency of the 17q21.31 microdeletion syndrome is estimated to be in the order of 0.64% (95% CI, 0.35%-0.93%) of individuals with unexplained intellectual disability, indicating that the 17q21.31 deletion syndrome is currently greatly underdiagnosed in individuals with intellectual disability [Koolen et al 2008].

The prevalence of the 17q21.31 deletion syndrome in the population as a whole is estimated at approximately one in 16,000 individuals [Koolen et al 2008].

The 17q21.31 deletion 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 17q21.31 microdeletion 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

• Brain imaging studies in individuals with microcephaly and/or seizures

• If seizures are suspected, consultation with a neurologist

• 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 of hypermetropia and strabismus

• Monitoring for spine deformities secondary to muscle weakness

• Monitoring as needed of cardiac and renal/urologic abnormalities

Testing of Relatives at Risk

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

Therapies Under Investigation

Search Clinical Trials.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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

The 17q21.31 microdeletion syndrome 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 deletions detected are de novo, except for one family. Thus, most affected individuals are simplex cases (i.e., a single occurrence in a family). Balanced rearrangements in the parents or the same finding as in the child has not been reported. A 17q21.31 deletion has been identified in two maternal half-siblings, whose mother did not carry the rearrangement in her somatic cells [Author, personal observation].

• The recurrence risk for future pregnancies is low (probably <1%) but greater than that of the general population because parents may have (a) germline mosaicism, or (b) low-level somatic mosaicism that also includes the germline, or (c) a balanced chromosomal rearrangement involving 17q21.31.

Sibs of a proband

• The risk to the sibs of the proband depends on the status of the parents. In the unlikely event that a parent has germline mosaicism for a 17q21.31 deletion or a balanced structural chromosome rearrangement involving the 17q21.31 region, the risk to sibs is increased and depends on the specific chromosome rearrangement.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low because to date only one familial case has been reported.

Offspring of a proband. No individuals diagnosed with 17q21.31 microdeletion syndrome have been known to reproduce. Individuals who have the 17q21.31 deletion would be expected to have a 50% chance of transmitting the deletion to each child.

Other family members. In one family reported to date, a 17q21.31 deletion was identified in two maternal half-siblings, whose mother did not carry the rearrangement in her somatic cells [Author, personal observation].

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. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 17q21.31 microdeletion 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 the 17q21.31 microdeletion syndrome because of the recurrence risk (probably <1%) associated with the possibility of germline mosaicism or inversion polymorphism.

Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using FISH in the same manner described in 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 unaffected individuals in whom a balanced chromosome rearrangement involving the 17q21.31 region has been established. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

The 17q21.31 region contains multiple polymorphic copy number variants (CNVs) that are also found in the general population (see projects.tcag.ca/variation), complicating the definition of the precise deletion breakpoints. So far, all deletions described are between 500 kb and 650 kb [Koolen et al 2006, Sharp et al 2006, Shaw-Smith et al 2006]. The difference in deletion size may reflect the extreme copy number polymorphism at the distal side rather than variation in the breakpoints [Koolen et al 2008]. Based on 250K SNP array analyses, a minimal 424-kb critical region (41046729-41470954 Mb, hg17) recurrently deleted in affected individuals but not in controls was delineated.

Further refinement of the deletions using ultra-high density oligonucleotide arrays revealed that the proximal breakpoints in affected individuals were contained within an interval of fewer than 500 bp within an L2 LINE motif, representing a possible hotspot for nonallelic homologous recombination (NAHR) [Koolen et al 2008]. So far, the distal breakpoint has not been defined precisely. The deletion seems to extend more distally in some affected individuals who were tested, although this could reflect the extreme copy number polymorphism at the distal side rather than variation in the breakpoints. Future deep sequencing to characterize the H2-sequence and determine if a common distal breakpoint exists will be relevant to prove NAHR as the underlying mechanism for de novo occurrence of the 17q21.31 microdeletion.

The 424-kb critical region encompasses at least six genes, C17orf69, CRHR1, IMP5, MAPT, STH, and KIAA1267. Haploinsufficiency of one or more of these genes may underlie the phenotype seen in individuals with the 17q21.31 deletion syndrome. MAPT is of particular interest, as the gene is highly expressed in brain and is involved in several neurodegenerative diseases [Rademakers et al 2004].

The 17q21.31 genomic interval contains a common 900-kb inversion polymorphism, resulting in a haplotype block with two highly divergent haplotypes designated H1 and H2 [Stefansson et al 2005]. Zody et al [2008] show that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with intellectual disability in European populations. In every parent-child trio tested to date, the parent originating the deleted chromosome 17 carries at least one H2 chromosome, 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 low-copy-repeat 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].

Literature Cited

1. 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]
2. 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]
3. 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, 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]
4. 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]
5. Lupski JR. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 1998;14:417–22. [PubMed: 9820031]
6. Lupski JR. Genome structural variation and sporadic disease traits. Nat Genet. 2006;38:974–6. [PubMed: 16941003]
7. Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat. 2004;24:277–95. [PubMed: 15365985]
8. 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]
9. 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]
10. 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]
11. 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, Savarirayan R, Peters G. Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome. J Med Genet. 2009;46:480–9. [PubMed: 19447831]
12. Varela MC, Krepischi-Santos AC, Paz JA, Knijnenburg J, Szuhai K, Rosenberg C, Koiffmann CP. A 17q21.31 microdeletion encompassing the MAPT gene in a mentally impaired patient. Cytogenet Genome Res. 2006;114:89–92. [PubMed: 16717456]
13. 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]

Acknowledgments

The authors gratefully acknowledge the members of C17 support group and other parents for their participation in research and for their generous sharing of information.

Revision History

• 26 January 2010 (me) Review posted live

• 28 August 2009 (dak) Original submission