microarray CGH (aCGH)

Scientific background

With the introduction of high-resolution techniques and fluorescence in situ hybridization (FISH), an increasing number of clinical syndromes have been found to be caused by microdeletions. Microdeletion syndromes usually lead to complex yet clinically distinguishable phenotypes and usually occur sporadically as an isolated case within a family. Most of the chromosomal microdeletion syndromes that are based on the loss of mainly submicroscopic chromosomal segments are associated with intellectual disability. However, other symptoms such as specific combinations of malformations and/or dysmorphic signs and characteristic “behavioral phenotypes” are almost always prominent. In these cases, there is usually a suspected clinical diagnosis that requires a specific examination. Some of the microdeletion syndromes belong to the more common genetic disorders, especially the microdeletion 22q11.2 which causes DiGeorge syndrome and is observed with a frequency of at least 1:4,000. Most of the microdeletion syndromes are also called contiguous gene syndromes as the symptoms are most likely caused by the loss of several genes located in the deleted region.


A list of some important microdeletion syndromes which are regularly analyzed is given below. Some of the syndromes mentioned may also have other causes (single gene mutation, e.g., in Angelman syndrome (AS) and/or uniparental disomy, e.g., in Prader-Willi syndrome and AS).


Classic microdeletion syndromes:


  • Angelman syndrome (15q11-q13)
  • Cri-du-chat syndrome (5p15.2-p15.3)
  • DiGeorge syndrome (22q11.2)
  • Miller-Dieker syndrome (17p13.3)
  • Prader-Willi syndrome (15q11-q13)
  • Shprintzen syndrome (22q11.2)
  • Smith-Magenis syndrome (17p11.2)
  • Williams-Beuren syndrome (7q11.23)
  • Wolf-Hirschhorn syndrome (4p16.3)


The use of chromosomal microarrays has identified numerous new microdeletion and duplication syndromes which were unknown a few years ago and whose phenotype was only recognized as characteristic after repeated descriptions of the same imbalance.


Newer microdeletion and duplication syndromes with intellectual disability as a leading symptom:


  • Microdeletion 1q21.1
  • Microduplication 1q21.1
  • Microdeletion 1p36
  • Microdeletion 1q41q42
  • Microdeletion 2p15p16.1
  • Microdeletion 3q29
  • Microduplication 7q11.23
  • Microdeletion 9q22.3
  • Microdeletion/duplication 10q11.21-q11.23
  • Microdeletion 12q14
  • Microdeletion 14q11.2
  • Microdeletion 15q11.2 (Burnside-Butler syndrome)
  • Microdeletion 15q13.3
  • Microdeletion 15q24 (Witteveen-Kolk syndrome)
  • Microdeletion/duplication 16p11.2
  • Microdeletion 16p11.2p12.2
  • Microdeletion 16p13.1
  • Microduplication 16p13.1
  • Microduplication 17p11.2 (Potocki-Lupski syndrome)
  • Microdeletion 17q21.31 (Koolen-De Vries syndrome)
  • Microdeletion 19q13.11
  • Distal microdeletion 22q11.2
  • Microduplication 22q11.2
  • Microduplication Xq28


Lists modified from Vissers et al. 2010, J Med Genet 47:289, Slavotinek 2008,Hum Genet 124:1 and Watson et al. 2014, Annu Rev Genome Hum Genet 15:215.




Goldenberg 2018, Pediatr Ann 47(5):e198 / Watson et al. 2014, Annu Rev Genome Hum Genet 15:215 / Vissers et al. 2010, J Med Genet 47:289 / Slavotinek 2008, Hum Genet 124:1/ Rost and Klein 2005, J Lab Med 29:152 / Seller et al. 2002, Clin Dysmorphol 11:113 / Dekeersmaker et al. 2002, Prenat Diagn 22:366 / Rost 2000, Monatsschr Kinderheilkd 148:55

The scientific background of some important microdeletion and microduplication syndromes and aneuploidies is given below.




Cri du chat syndrome, like Wolf-Hirschhorn syndrome, does not strictly belong to the group of microdeletion syndromes, since the deletion on the short arm of chromosome 5 is often of a size that is already visible in conventional chromosomal analysis. Smaller deletions can be detected by molecular cytogenetics or by chromosomal microarrays (CMA). Deletion 5p is one of the most common autosomal deletions with a frequency of about 1:15,000 to 1:50,000. About 80% are de novo deletions and about 10 to 15% result from a parental balanced structural aberration.


The syndrome name is derived from the striking high-pitched cry of affected newborns, which is pathognomonic for the syndrome. The infants usually have muscle hypotonia, microcephaly, epicanthus and downward slanting eyelid folds, clinodactyly and, occasionally, cardiac defects. Development is significantly delayed, especially with regards to speech, and the IQ of adolescents and adults is in the range of the most severe intellectual disability (< 20). Life expectancy is not significantly reduced unless complex cardiac defects are present. With smaller or interstitial deletions, patients often have only partial symptoms, such as the prominent cry as newborns but with no signs of dysmorphia or a less pronounced developmental disorder.



Elmakky et al. 2014, Eur J Med Genet 57:145 / Mainardi 2006, Orphanet J Rare Dis I:33 / Zhang et al. 2005, Am J Hum Genet 76:312




DiGeorge syndrome represents a part of the highly variable clinical spectrum of the microdeletion 22q11.2. It is caused by a developmental defect of the third and fourth pharyngeal pouches or derived structures such as the thymus and parathyroid glands and the fourth gill arch. In the complete clinical picture, thymic hypoplasia or aplasia is found, resulting in a cellular immunity defect. In about 10% a severe immunodeficiency is present. In about 60% there is hypoplasia of the parathyroid glands, which may cause hypocalcemia and is sometimes accompanied by seizures. Hypocalcemia usually develops in the neonatal period, but may occur later. Calcium levels can normalize spontaneously at any time, but long-term calcium substitution is often required. Heart defects are another leading symptom, and aortic arch anomalies, conotruncal heart defects such as tetralogy of Fallot or truncus arteriosus, but also ventricular septal defects or patent ductus arteriosus have been observed. Cleft palate also occurs. Signs of velopharyngeal insufficiency include a hoarse voice or nasal speech later on.


Almost all patients have a mild developmental delay, and about 30 to 40% have short stature. External features include hypertelorism, epicanthus, a small mouth with a curved upper lip, microretrognathia, and round, wide ears.


In about 5 to 10% of cases, microdeletion 22q11.2 is inherited from one parent. Therefore, an examination of the parents of an affected child is recommended, especially for future family planning purposes.



Goldenberg 2018, Pediatr Ann, 47(5):e198 / Momma 2007, Int J Cardiol 114:147 / Arinami 2006, J Hum Genet 51:1037 / Simon et al. 2005, Dev Psychopathol 17:753 / Bassett 2005, Am J Med Genet 138A:307 / Sullivan 2004, Curr Opin Allergy Klin Immunol 4:505 / Yamagishi and Keio 2002, Med 51:77 / Jawad 2001, J Pediat 139:715 / Scambler 2000, Hum Mol Genet 9 16:2421 / Rost 2000, Monatsschr Kinderheilkd, 148:55 / Ryan et al. 1997, J Med Genet 34:798




Double Y syndrome or 47, XYY syndrome has an incidence of approximately 1:1,000 in male newborns. In most cases, a 47, XYY karyotype is found, and in rare cases, X and Y polysomies. Characteristically, patients show increased height, but are otherwise physically inconspicuous and usually have normal fertility. IQ is mostly normal. Motor development may be slightly delayed. Reading and language difficulties may cause emotional disturbances and reduced frustration tolerance, so that psychological-educational care is advised in childhood if abnormalities are present. Scientific studies have shown that boys and men with an XYY pattern who are in a stable familial environment are not more likely to develop behavioral problems than others. Offspring of XYY males have no increased risk of gonosomal aneuploidies.



Ross et al. 2009, Dev Disabil Res Rev 15:309 / Ratcliffe et al. 1999, Arch Dis Child 80:1892 / Bender et al. 1984, Clin Genet 25:435 / Valentine et al. 1997, Birth Defects OAS XV:175




Down syndrome is caused by an additional chromosome 21 (trisomy 21). Life expectancy has increased significantly in recent years, but is reduced by about 20 years compared to the general population. Clinical symptoms include intellectual disability, typical facial features (epicanthus, upward slanting eyes, macroglossia), cardiac abnormalities, muscle hypotonia, sandal gap, and a single transverse palmar crease. Females with Down syndrome are fertile, whereas males are usually infertile. An increased susceptibility to infections and a slightly increased risk of childhood leukemia are characteristic of Down syndrome.


There are very good support options available for those with Down syndrome to help them achieve a high degree of independence in adulthood. Nevertheless, most adults with Down syndrome are reliant on support in their daily lives. Down syndrome occurs with an average incidence of 1:650 newborns, although there is a maternal age effect (incidence 1:1,250 in a 20-year-old woman and 1:90 in a 40-year-old woman). In 92% an additional chromosome 21 is present (free trisomy 21), 3% show a mosaic trisomy 21 and in 5% a so-called Robertsonian translocation between a third chromosome 21 and an acrocentric chromosome is found (so-called hereditary variant of Down syndrome). Partial trisomies due to other translocations are very rare.



Antonorakis et al. 2004, Nature Rev Genet 5:725 / Stripoli et al. 1999, Genomics 64:252 / Yamakawa et al. 1998, Hum Molec Genet 7:227 / Baird and Sadovnick 1988, Lancet 2:1354 / Pellisier et al. 1988, Hum Genet 80: 277




Edwards syndrome, which is based on trisomy 18, has an average incidence of 1:3,000 in newborns. In 80% a free trisomy 18 is found, in 10% a mosaic trisomy and in another 10% there is an unbalanced translocation. There is clear gynecotrophy with 75% female patients. External symptoms are variable; they include dolichocephaly with prominent occiput and a small face, ear dysplasia, microcephaly, microretrognathia, and a prominent calcaneus. Overlapping of the 3rd and 4th fingers by the 2nd and 5th fingers is characteristic, especially in newborns. Furthermore, heart defects, horseshoe kidney, muscle hypertonia and joint contractures are found. Psychomotor development is also severely delayed. Mortality usually occurs within the first few months of life, with over 90% dying within the first year of life. As with all autosomal trisomies, there is a maternal age effect.



Vendola et al. 2010, Am J Med Genet 152A:360 / Baty et al. 1994, Am J Med Genet 49:175 / Van Dyke and Allen 1990, Pediatrics 85:753 / Carter et al. 1983, Clin Genet 27:59




Klinefelter syndrome has a prevalence of approximately 1:1,000 in male newborns. 80% of affected individuals have a pure 47,XXY karyotype, while the remaining 20% have mosaicism or other X polysomies. In childhood, discrete abnormalities in psychomotor development may be present, as well as passive behavior and learning difficulties. During puberty, hypergonadotropic hypogonadism develops with the underdevelopment of secondary sexual characteristics and azoospermia, as well as tall stature with increased fat in the trunk and possibly gynecomastia. Osteoporosis may occur later. Intelligence is usually within the normal range or 5-10 IQ points below the family average. From puberty onward, testosterone substitution should be performed where there are subnormal values and for osteoporosis prophylaxis.



Ogata et al. 2001, Am J Med Genet 98:353 / Ogata et al. 2001, J Med Genet 38:1




Microdeletion 1p36 is probably the most common terminal microdeletion occurring with a frequency of 1:5,000 to 1:10,000. It causes 1p36 microdeletion syndrome also known as monosomy 1p36 syndrome. Most patients have a moderate to severe developmental disorder with severe impairment of expressive speech, muscle hypotonia, and growth retardation. External features include: a large anterior fontanel that closes late, deep-set eyes, horizontal eyebrows, broad nasal root, hypoplastic midface, low-set dysplastic ears, very pointed chin, brachydactyly and camptodactyly, and short feet. Obesity and hyperphagia are described in some patients. Congenital heart defects are present in about 70% and noncompaction cardiomyopathy in 23%. Almost all patients present with abnormal ECG, and nearly half also have seizures. Visual and hearing disturbances are also present in more than half of the patients.


Microdeletion 1p36 is usually detected by subtelomeric diagnosis or increasingly by chromosomal microarray; in individual cases, it can be diagnosed by light microscopy using a high-resolution banding technique (between 600 and 800 bands) in chromosomal analysis.



D’Angelo et al. 2010, Am J Med Genet 152A:102 / Battaglia 2005, Brain Dev 27:358 / Slavotinek et al. 1999, J Med Genet 36:657 / Shapira et al. 1997, Am J Hum Genet 61:642




Microdeletion 22q11.2, which causes 22q11.2 deletion syndrome, is the most common microdeletion with the highest variability of clinical symptoms; the incidence is at least 1:4,000. The severe presentation is defined by the complete clinical picture of DiGeorge syndrome with complex heart defects, thymic aplasia and resulting immunodeficiency, hypoparathyroidism due to aplasia of the parathyroid glands, developmental delay and short stature. The mild presentation shows only discrete signs of dysmorphia, possibly short stature and a hoarse voice. There is an overlap between the individual syndromes and even within a family, the degree of expression can vary significantly. The cause of this high variability—even with the same deletion—is not yet clear.


Microdeletion 22q11.2 causes a developmental field defect affecting the 3rd and 4th pharyngeal pockets as well as of the 4th gill arch and the structures deriving from it, such as vessels close to the heart, thymus, parathyroid glands. 75% of patients have heart defects, especially aortic arch anomalies and conotruncal heart defects. Up to 70% of patients have hypocalcemia, at least temporarily. External features include a slightly increased interocular distance with a flat nasal root, hypoplastic nostrils, a narrow mouth with an arched upper lip overhanging the lower lip, and retrognathia. In adulthood, psychiatric abnormalities are reported in up to 20% of patients. In rare infantile psychosis, microdeletion 22q11.2 is part of the differential diagnosis. In 5-10% of patients the microdeletion is present in one parent, which leads to a 50% risk of recurrence for future children. Therefore, the parents of an affected child should also be examined, especially for family planning purposes.



Goldenberg 2018, Pediat Ann 47(5):e198 / Kobrynski et al. 2007, Lancet 370:1443 / Momma 2007, Int J Cardiol 114:147 / Yamagishi 2002, Keio J Med 51:77 / Scambler 2000, Hum Mol Genet 9, 16:2421 / Rost I 2000, Monatsschr Kinderheilkd, 148:55 / Ryan et al. 1997, J Med Genet 34: 798




Phelan-McDermaid syndrome is caused by microdeletion 22q13.3 that affects the terminal end of the long arm of chromosome 22: this is not the region 22q11.2 known to be affected in DiGeorge syndrome. Some patients have deletions detectable by light microscopy, while others have deletions that can only be detected by FISH analysis or chromosomal microarray. In approximately one third of patients, the deletion is a consequence of a chromosomal translocation.


The main symptom of microdeletion 22q13.3 is pronounced muscle hypotonia that is usually already present at birth. Therefore, this microdeletion can be included as a differential diagnosis of severe hypotonia in a newborn. In addition, developmental delay occurs later which mainly affects speech and may even lead to the absence of expressive speech. Normal to large body measurements are characteristic. Autistic behavior has been described in some patients. External features are discrete and inconspicuous and seem to vary depending on the size of the deletion: dolichocephaly, ear dysplasia, epicanthal fold, droopy eyelids (ptosis), periorbital soft tissue fullness, deformed philtrum, full lips, pronounced chin, syndactyly of second and third toes, dysplastic toenails. Seizures occur in nearly one third of patients.


The smallest overlapping deletion region contains the SHANK3/ProSAP2 gene whose haploinsufficiency is thought to cause most of the neurological symptoms of Phelan-McDermid syndrome. The gene product functions as a scaffolding protein in postsynaptic structures of excitatory synapses and binds to neuroligins that are also associated with autistic disorders.



Harony-Nicolas et al. 2015, J Child Neurol 30(14):1861 / Sykes et al. 2009, EJHG 17:1347 / Phelan 2008, OJRD 3:14 / Cusmano-Ozog et al. 2007, AM J Med Genet 145C:393 / Lindquist et al. 2005, Clin Dysmorphol 14:55 / Manning et al. 2004, Pediatrics 114, 2:451 / Phelan et al. 2001, Am J Med Genet 101:91




Although microdeletion 22q11.2 occurs with a prevalence of up to 1:4,000, microduplications of the same region are only observed about half as often. This is despite the expectation that the underlying mechanism (non-allelic homologous recombination (NAHR) in a region of low copy repeats) would cause microduplications of the same region to occur as frequently. It may be partly due to the highly variable or mild phenotype which leads to a diagnosis in only a few cases. Furthermore, in the usual FISH analysis of metaphases, a duplication (two close signals) is more difficult to detect than a deletion (missing signal). For duplication diagnostics, FISH analysis of interphase cell nuclei is more suitable. Alternatively, multiplex ligation-dependent amplification (MLPA) and chromosomal microarray (CMA) may be considered. Most patients have a duplication of about 1.5 to 3 Mb, which is often present in one parent who is usually clinically inconspicuous.


The clinical symptoms of microduplication 22q11.2 are also highly variable within a family and may overlap with microdeletion 22q11.2. They range from cardiac and urogenital malformations, velopharyngeal insufficiency, mild learning difficulties and autism spectrum disorders to asymptomatic duplication carriers. Externally, high-set eyebrows, wide interocular distance with eyelids sloping outwards and downwards, mild micro/retrognathia, and minor ear dysplasia are observed. Hearing impairment is present in almost half of the patients. The duplicated region contains the TBX1 gene. With a microdeletion, the loss of TBX1 is responsible for most of the symptoms. In the mouse model, it has been shown that overexpression of TBX1 as a result of a duplication causes similar symptoms to haploinsufficiency. This may explain the overlap of symptoms between microdeletion and microduplication 22q11.2.



Goldenberg 2018, Pediatr Ann 47(5):e198 / Portnoi 2009, Eur J Med Genet 52:88 / de La Rochebrochard et al. 2006, Am J Med Genet 114:1608 / Yobb et al. 2005, Am J Hum Genet 76:865 / Portnoi et al. 2005, Am J Med Genet 137A:47 / Ensenauer et al. 2003, Am J Hum Genet 73:1027




Miller-Dieker syndrome (MDS) is characterized by lissencephaly (in Greek lissos=smooth). It is a severe early embryonic developmental disorder of the cerebral cortex that results in a reduction in the number of cell layers from 6 (normal) to 3-4 and decreased to absent gyration (agyria or pachygyria seen by MRI) of the brain surface. A corpus callosum deficiency is often found. Accordingly, the children show severe developmental delay usually accompanied by early-onset seizures and feeding difficulties that may also lead to aspiration and pneumonia. Life expectancy is reduced. External features include a high arched forehead with bitemporal hollowing, microcephaly, a short nose with upturned nostrils, an arched prominent upper lip, and posteriorly rotated ears. MDS is caused by a microdeletion at the terminal end of the short arm of chromosome 17 (17p13.3). The migration disorder is caused by deletion of the LIS1 or PAFAH1B1 gene. The complex phenotype of MDS with severe lissencephaly, additional growth deficiency, facial abnormalities and occasionally other malformations is caused by the additional deletion of the YWHAE gene as part of a contiguous gene syndrome. About 80% of the deletions in MDS are new and about 20% result from a balanced parental structural change.



Chen et al. 2018, Taiwan J Obstet Gynecol 57(5):765 / Screenath Nagamani et al. 2009, J Med Genet 46:825 / Matarese et al. 2009, Pediatric Neurology 40:324 / Spalice et al. 2009, Acta Paediatrica 98:421 / Kato and Dobyns 2003, Hum Mol Genet 12:R89 / Rost 2000, Monatsschr Kinderheilkd 148:55 / Dobyns et al. 1991, Am J Hum Genet 48:584




The average incidence of Patau syndrome is estimated to be 1:5,000 newborns. Free trisomy 13 is detected in 75%, mosaic trisomy in 5%, and an unbalanced translocation in 20%. The characteristic external abnormalities include a usually bilateral cleft lip and palate, various eye defects (microophthalmia, anophthalmia, coloboma), microcephaly, hexadactyly, ear dysplasia, scalp defects, and omphalocele. Organ malformations include heart defects and cystic kidneys and CNS anomalies such as arhinecephaly or holoprosencephaly. Psychomotor development is severely impaired. About 50% of the patients die within the first month of life and more than 90% within the first year of life.



Vendola et al. 2010, Am J Med Genet 152A:360 / Wyllie et al. 1994, Arch Dis Child 71:343 / Baty et al. 1994, Am J Med Genet 49:189 / Fujinaga et al. 1990, Teratology 41:233 / Hassold et al. 1987, J Med Genet 24:725




Prader-Willi syndrome (PWS) is characterized by severe muscle hypotonia with feeding difficulties and failure to thrive in infancy. Decreased fetal movements may be evident during pregnancy, and delivery may occur from a breech presentation. Motor development is moderately delayed meaning children can sit at one year of age on average and walk freely at two years of age. There is mild intellectual disability with approximately 40% of children having intelligence at the lower end of the normal range. Nevertheless, learning difficulties are common. Beyond infancy, hyperphagia occurs leading to obesity and subsequent complications such as diabetes mellitus and cardiopulmonary disease. Children have short stature in most cases. There is hypogenitalism or hypogonadism with low hormone levels, and the onset of puberty is often not age-appropriate. Typical behaviors include stubbornness and temper tantrums, as well as skin picking with a tendency to self-injury. Patients have good visual comprehension and processing skills, e.g., putting puzzles together. External features often include a narrow face, almond-shaped eyes, strabismus, a small mouth with a narrow upper lip, and small hands and feet.


Most patients with a microdeletion as the cause of PWS have some degree of hypopigmentation. The incidence is reported to be 1:15,000 to 1:30,000. The disease-causing genes in PWS (and Angelman syndrome) are located in a chromosomal region (15q11.2-q13) that is susceptible to so-called genomic imprinting. This parental imprinting causes genes to vary in the level of DNA methylation, chromatin structure, and thus expression, depending on which parent they originate from. This is controlled by a two-part imprinting center in 15q11.2-q13. Because of this unique feature, Prader-Willi syndrome and Angelman syndrome may have other causes besides a microdeletion, which lead to loss of expression of the affected genes. Several genes in the region 15q11.2-q13 are expressed only from paternal chromosome 15 and are causally related to PWS. Approximately 70% of PWS patients have a microdeletion 15q11.2-q13 on chromosome 15 inherited from the father. About 30% have a maternal uniparental disomy 15 (UPD), i.e., both of the chromosome 15 originate from the mother and none from the father. About 1% have a disorder in the imprinting center, and in a few cases a chromosomal structural aberration involving the region 15q11.2-q13 was found. There are certain genotype-phenotype correlations. Molecular cytogenetic (FISH) analysis detects only microdeletion, while methylation sensitive PCR detects microdeletion, UPD and imprinting mutation without specification.



Butler et al. 2018, Am J Med Genet A 176(2):368 / Cassidy et al. 2009, Eur J Hum Genet 17:3 / Leitlinien der Deutschen Gesellschaft für Humangenetik und dem Berufsverband der Deutschen Humangenetiker e.V. 2010, medgen 22:282 / Sarimski 2003: Prader-Willi-Syndrom, in: Entwicklungspsychologie genetischer Syndrome, 3.Aufl. Hogrefe, Göttingen / Rost 2000, Monatsschr Kinderheilkd 148:55 / Zeschnigk et al. 1997, Eur J Hum Genet 5:94 / Holm et al. 1993, Pediatrics 91:398




Like DiGeorge syndrome, Shprintzen syndrome or velocardiofacial syndrome (VCFS) belongs to the group of syndromes caused by the microdeletion 22q11.2 and can be categorized under this general term. The main symptoms are heart defects in 85% of cases, cleft palate, velopharyngeal insufficiency with nasal speech and learning disabilities; characteristic phenotypic features such as broad nasal bridge, long nose, nostril hypoplasia, and graceful build with long slender hands and feet are also seen. About 1/3 of the patients have a short stature. Further characteristics are conspicuous behaviors such as extreme reticence and shyness. In up to 25% of adults, schizophrenic psychoses may occur. Hypoplasia or aplasia of the thymus and parathyroid glands are less common than in DiGeorge syndrome. However, there are overlaps with DiGeorge syndrome, and in some patients, a clear diagnosis between the two syndromes is not possible. In approximately 5 to 10% of cases, the microdeletion 22q11.2 has been inherited from one of the parents. Therefore, the parents should be examined to exclude the microdeletion, especially for further family planning purposes.



Goldenberg 2018, Pediatr Ann 47(5):e198 / Momma 2007, Int J Cardiol 114:147 / Arinami 2006, J Hum Genet 51:1037 / Simon et al. 2005, Dev Psychopathol 17:753 / Bassett 2005, Am J Med Genet 138A:307 / Sullivan 2004, Curr Opin Allergy Klin Immunol 4:505 / Yamagishi and Keio 2002, Med 51:77 / Jawad 2001, J Pediat 139:715 / Scambler 2000, Hum Mol Genet 9, 16:2421 / Rost 2000, Monatsschr Kinderheilkd, 148:55 / Ryan et al. 1997, J Med Genet 34:798




Smith-Magenis syndrome (SMS) is a global developmental delay disorder associated with typical behaviors and discrete external features, such as brachycephaly, flat midface, broad nasal bridge, M-shaped curved upper lip with distinct philtrum, brachydactyly, and forearm limitations in infancy and early childhood. The voice is often low and hoarse. Up to 70% of patients have hearing loss, often as a result of chronic middle ear infections (80-90%). About 30% have congenital malformations of the heart and/or kidneys. Foot deformities are common. Approximately 50% have myopia and occasionally related retinal detachment. Tantrums, self-harming behavior and significant sleep disorders are typical in SMS and can be very stressful for families. Many children with SMS are described as musical and most are good with computers, which can be used for support. The prevalence is reported to be 1:15,000 to 1:25,000. However, SMS is probably underdiagnosed.


SMS is caused by a microdeletion of variable size (ranging from 1.5 to 9 Mb, usually about 3.7 Mb) on the short arm of chromosome 17 (17p11.2) involving the RAI1 gene in 90% of cases and a pathogenic variant in the RAI1 gene in 10% of cases. The RAI1 gene is responsible for most of the symptoms of SMS. An additional 13 genes located in the deleted region modify the severity (contiguous gene syndrome). The microdeletion or variant almost always occurs de novo. Consequently, the risk of recurrence is low if a parental chromosomal structural change in chromosome 17 or a rare parental mosaic for a RAI1 variant have been ruled out. Large deletions can be found with conventional chromosomal analysis, and the more common small ones with FISH analysis or a chromosomal microarray.



Nag et al. 2019, J Intellect Disab 23(3):359 / Goldenberg 2018, Pediatr Ann 47(5):e198 / Elsea et al. 2008, Eur J Hum Genet 16:412 / Rost 2000, Monatsschr Kinderheilkd 148:55 / Greenberg et al. 1996, Am J Med Genet 62:247




Triple X syndrome, also known as 47,XXX syndrome or trisomy X, is characterized by a trisomy of the X chromosome. Patients do not usually show significant physical symptoms apart from above average height. As the clinical impact is highly variable, many women with triple X are never diagnosed with this chromosomal aberration. About 70% of women are fertile, but some present with menstrual irregularities and premature menopause. Intelligence may be 10-15 points below the family average. Speech development may be delayed. Offspring of triple X women are not found to be at a higher risk for gonosomal aneuploidy.


The prevalence of triple X syndrome is reported to be approximately 1:1,000 in female newborns. In 98% of patients, trisomy X is found in all cells, while 2% show mosaicism.


Ogata et al. 2001, J Med Genet 38:1 / Müller-Henbach et al. 1977, Am J Obstet Gynecol 127:211




Turner syndrome is one of the most common chromosomal disorders with an incidence of 1:2,500 in female newborns and an estimated 1:100 conceptions (98% of these pregnancies end in miscarriage in the 1st trimester). Prenatal ultrasound may reveal early hygroma colli or hydrops fetalis which often leads to invasive prenatal screening and detection of the chromosomal disorder. The clinical manifestations are short stature (approximately 150 cm), primary amenorrhea, streak gonads, a webbed neck and slight facial dysmorphic signs such as outwardly sloping eyelids. Intelligence is within the normal range. Prenatally, dilatation of the lymphatic vessels with lymphedema and cystic hygroma is common. Hormone treatment is necessary for the development of secondary sexual characteristics. Although there is no growth hormone deficiency, growth in many patients can be improved by supplementary growth hormone therapy. Where there is 45,X/46,XY mosaicism, sonographic monitoring of the gonads is recommended due to an increased risk of gonadoblastoma. Noonan syndrome should be considered as the primary differential diagnosis.


In about 55% of patients, a complete monosomy X is present, whereas in the remaining patients, there are gonosomal mosaics or X-linked structural anomalies.



Boucher et al. 2001, J Med Genet 38:591 / Ogata et al. 2001, J Med Genet 38:1 / Wieacker 2001, Medgen 13:3 / Tarani et al. 1998, Gynecol Endocrinol 12:83 / Swillen et al. 1993, Genet Counsel 4:7




Uniparental disomy (UPD) refers to a condition in which an individual has inherited both copies (alleles) or parts of a chromosome from only one parent. It is called isodisomy if a single parental chromosome is duplicated or heterodisomy if there are two different copies of one chromosome from one parent. For most chromosomes, the condition is likely to have no pathological significance. However, if the chromosome that is inherited by isodisomy carries a variant in a recessive gene, it will be homozygous in the offspring due to duplication of this chromosome or gene and cause the disease. Alternatively, if a chromosome or chromosomal region contains genes that are affected by genomic imprinting, i.e. that are active or inactive depending on the parental origin, is inherited, this may lead to complications. This plays a role in Prader-Willi syndrome and Angelman syndrome. UPD diagnostics also has functional significance in prenatal diagnostics. For example, if chorionic villus sampling shows a mosaic is present for a trisomy of one of the chromosomes known to have pathological effects with UPD, it is necessary to investigate whether UPD has occurred in the unborn child by, for instance, “trisomy correction”. If the initial zygote was trisomic, i.e., it carried two chromosomes of the same type from one parent and one chromosome from the other parent, a “trisomy correction” can result in loss of the single chromosome copy from one parent. The two chromosomes from the other parent remain which suggests a normal condition but may have pathological effects.


Robertsonian translocations involving chromosomes 14 and 15 also require prenatal diagnostics to exclude UDP, although the risk is most likely less than 1%. Apart from the chromosomes listed below, in which an UPD can cause a disease, the literature also provides evidence for chromosomes 2, 3, 16 and 20; therefore, if a trisomy is present, even in mosaic form, a prenatal diagnosis should exclude an UPD.


The most common disorders caused by UPD (most are heterogeneous and may also have other other causes, e.g., Prader-Willi syndrome, Angelman syndrome, or Beckwith-Wiedemann syndrome):

  • 6q23-24, paternal, transient neonatal diabetes mellitus
  • 7p11-13, maternal, Silver-Russell syndrome, primordial short stature (also chromosome 11)
  • 11p15.5, paternal (in mosaic form), Beckwith-Wiedemann syndrome (EMG syndrome)
  • 14, paternal, intrauterine growth retardation, malformations, severe developmental delay
  • 14, maternal, pre- and postnatal growth retardation, mild developmental delay, dysmorphic signs
  • 15q11-13, maternal, Prader-Willi syndrome
  • 15q11-13, paternal, Angelman syndrome



Eggermann et al. 2015, Trends Mol Med 21(2):77 / Kotzot 2008, J Med Genet 45:545 / Kotzot 2008, Ultrasound Obstet Gynecol 31:100 / Engel 2006, Eur J Hum Genet 14:1158 / Kotzot 2002, Am J Med Genet 111:366 / Buiting et al. 2001, Medizinische Genetik 13:124




Williams-Beuren syndrome (WBS), also known as Williams syndrome, is characterized by a combination of cardiovascular malformations, particularly supravalvular aortic stenosis (SVAS) and/or (peripheral) pulmonary stenosis, mild developmental delay, and distinctive external and behavioral features. Renal artery stenosis with the development of arterial hypertension can also occur. An early visual diagnosis may be possible based on external features (puffiness around the eyelids, eyebrows that are thinner in the middle, blue iris with a star-shaped pattern, full lips, especially the lower lip, micrognathia, hoarse voice, and small, widely spaced teeth). Infants and toddlers fail to thrive and digestive disorders are often found. Hernias and joint hyperextensibility are an indication of connective tissue weakness. Transient hypercalcemia is present in over 50% of cases. WBS patients show special abilities and behaviors despite their developmental delay. As toddlers they are rather shy, but later they become very sociable, eloquent and musically gifted. They mainly have difficulties in visual motor coordination, e.g, pattern recognition.


WBS is caused by a 1.5 to 1.8 Mb microdeletion in the long arm of chromosome 7 (7q11.23). There are 28 genes located in this region. Haploinsufficiency of the elastin gene is responsible for cardiovascular symptoms such as SVAS. Loss of the LIMK1, CLIP2, GTF2IRD1 and GTF2I genes are reported to cause the characteristic external and cognitive features. In most cases, the microdeletion occurs sporadically. However, there are occasional familial cases that follow an autosomal dominant inheritance pattern. The frequency is reported to be 1:7,500 to 1:20,000.



Goldenberg 2018, Pediatr Ann 47(5):e198 / Ferrero et al. 2010, Eur J Hum Genet 18:33 / Schubert 2009, Cell Mol Life Sci 66:1178 / Tassabehji 2003, Hum Mol Genet 12:R229 / Sarimski 2003: Williams-Beuren-Syndrom in: Entwicklungspsychologie genetischer Syndrome, 3. Aufl. Hogrefe, Göttingen / Rost 2000, Monatsschr Kinderheilkd 148:55




Wolf-Hirschhorn syndrome (WHS) is characterized by a combination of distinctive external features, congenital malformations, severe developmental delay and short stature. In many cases, a visual diagnosis is possible in a newborn or young infant. The patients have a wide distance between the eyes, a broad nasal root, arched eyebrows, outwards and downward sloping eyes, and strabismus (exotropia); colobomas, cleft lip and cleft palate, ear dysplasia, heart and kidney malformations, and hypospadias (in boys) are common. Approximately 80% of patients have seizures.


WHS is caused by deletions of different sizes of the terminal short arm of chromosome 4 (4p16.3). Smaller deletions (up to 3.5 Mb) are associated with a milder presentation without malformations, medium deletions (5 to 18 Mb) are associated with classic presentation of WHS, and very large deletions (22-25 Mb) are associated with a very severe presentation that bears no similarity to WHS. In classical WHS, the deletions are often detectable by conventional chromosomal analysis. Interstitial deletions with preserved subtelomeric regions also occur. Between 85 and 90% of the deletions are new, and the remainder are due to structural chromosomal rearrangements which may be present in the parents in a balanced form. The frequency is estimated at 1:20,000 to 1:50,000.



Battaglia et al. 2008, Am J Med Genet 148C:246 / Zollino et al. 2008, Am J Med Genet 148C:257 / Battaglia et al. 2001, Adv Pediatr 48:75 / Wright et al. 1998, Am J Med Genet 75:345


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