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Microdeletion and Microduplication Syndromes: An Update

Priya Ranganath, Prajnya Ranganath
Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, India
Correspondence to: Dr Prajnya Ranganath      Email: prajnyaranganath@gmail.com

1 Abstract

Microdeletion and microduplication syndromes (MMS) also known as ‘contiguous gene syndromes’ are a group of disorders caused by sub-microscopic chromosomal deletions or duplications. Most of these conditions are typically associated with developmental delay, autism, multiple congenital anomalies, and characteristic phenotypic features. These chromosomal abnormalities cannot be detected by conventional cytogenetic techniques like karyotyping and require higher resolution ‘molecular cytogenetic’ techniques. The advent of high throughput tests such as chromosomal microarray in the past one or two decades has led to a continuously growing list of microdeletions and microduplication syndromes along with identification of the ‘critical region’ responsible for the main phenotypic features associated with these syndromes. This review discusses the etiopathogenic mechanisms of MMS, some of the common MMS and their clinical features, the diagnostic tools available for their evaluation, and the databases available for analysis and interpretation.

2 Introduction

Microdeletion and microduplication syndromes (MMS) are a group of disorders, each of which has a typical pattern of manifestations which result from a small (<5Mb) deletion or duplication of a chromosomal segment spanning multiple disease genes, with each of the involved genes potentially contributing to the phenotype independently. These copy number variations (CNVs) are too small to be detected by conventional cytogenetic methods like karyotyping and hence require higher resolution cytogenetic techniques. The exact size and location for these may vary, but a specific “critical region” containing dosage sensitive genes responsible for the phenotype is generally involved (Goldenberg, 2018). Theoretically, for every microdeletion syndrome there should be a reciprocal microduplication syndrome, but microdeletions are more common. Microduplications appear to result in a milder or no clinical phenotype.

3 Molecular Etiopathology

Copy number variation (CNV) is defined as the gain or loss of a stretch of DNA when compared with the reference human genome and may range in size from a kilobase to several megabases or even an entire chromosome. The CNVs associated with MMS constitute only a small fraction of the total number of possible copy-number variants. There are two major classes of CNVs: recurrent and non-recurrent. Recurrent CNVs generally result from Non-Allelic Homologous Recombination (NAHR) during meiosis. In contrast, non-recurrent CNVs can occur as a result of Non-Homologous End Joining (NHEJ) or Fork Stalling and Template Switching (FoSTeS).

NAHR (LCR-mediated non-allelic homologous recombination):

LCRs are ‘low copy repeats’ of size 10 to 500 kilobase pairs (kb) and share 95% sequence identity (Watson et al.,2014). They are generally present in the pericentromeric regions and serve as substrates for NAHR (Figure 1).

 Figure 1: LCR-mediated non-allelic homologous recombination. The two large segmental duplications (depicted by blue arrows) with high sequence similarity flanking the region containing genes a, b, and c are LCRs (low copy repeats). During meiosis the homologous pair misalign due to the LCRs, resulting in abnormal cross over. This results in two reciprocal products: one chromosome carrying a duplication of the intervening region and therefore an additional copy of genes a, b, and c, and a second chromosome carrying a deletion of this same region. (adapted from Watson et al., 2014).

LCR-directed recombination happens between 2 homologous chromosomes, 2 sister chromatids of a single chromosome, within a chromatid (intrachromatid recombination) and between 2 non homologous chromosomes (Figure 2).

 Figure 2: LCR-directed chromosomal recombination: a) between 2 homologous chromosomes; b) between 2 sister chromatids of a single chromosome; c) within a chromatid (intrachromatid recombination); and d) between 2 non homologous chromosomes

NAHR mechanism favors deletions over duplications because deletions can result from crossovers both in cis and in trans whereas duplications can result from crossovers only in trans.

NHEJ (non-homologous end joining):

Unstable AT-rich palindromic sequences seen in the genome, are susceptible to double-stranded breaks. These breakpoints are repaired by a process referred to as non-homologous end jointing.

Broken ends of DNA are recognized by loading of the Ku70/Ku80 heterodimer which acts as a scaffold for recruitment of kinase and two subunit DNA ligase together with some accessory factors. This complex holds a pair of DNA ends together, forming a paired-end complex. The paired-end complex then ligates compatible DNA ends together, thus repairing the break (Watson et al.,2014; Harel & Lupski,2018).

NHEJ repairs double-stranded breaks at all stages of the cell cycle, bringing about the ligation of two DNA strands without the need for sequence homology, but is error-prone. In the process of joining the two sequences by NHEJ, the intervening fragment may get deleted, or an additional base may be incorporated at the junction (Figure 3).

 Figure 3: The molecular mechanism of non-homologous end joining (NHEJ). NHEJ involves binding of the KU heterodimer to double-stranded DNA ends, recruitment of DNA-PKcs (DNA-dependent protein kinase catalytic subunit), processing of ends, and recruitment of the DNA ligase IV (LIG4)-XRCC4 complex, which brings about ligation.
FoSTeS (Fork Stalling and Template Switching) (Harel & Lupski, 2018)

This happens due to undue lagging/stalling of the replication strand. This strand may move discontinuously within its own replication fork. It may disengage from the template strand and invade other replication forks as well. Using short regions of homology, it reinitiates replication elsewhere: within the same chromosome, the homologous chromosome, or a nonhomologous chromosome in proximity.

Depending on whether the same or a different chromosome has been invaded, the location of the strand, and whether the invasion is upstream or downstream relative to the original replication fork, the genetic material is deleted, inverted, or duplicated (Figure 4).


 Figure 4: Molecular mechanism for FoSTeS (Fork Stalling and Template Switching) (Adapted from: Tatevossian R. Molecular genetic analysis of paediatric low-grade astrocytoma. 2017; available at https://www.researchgate.net/)

4 Clinical Features

There are more than 120 clinically characterised microdeletion syndromes. With the advent of newer molecular diagnostic techniques for detecting copy number variations, new syndromes are being identified and reported regularly (Nevado et al., 2014; Zhang et al., 2016; Panigrahi et al.,2018). The phenotype of microduplication syndromes is often less clear and less well defined than for the corresponding microdeletion syndrome. In addition, some microduplication syndromes may be inherited from apparently normal parents raising important issues regarding incomplete penetrance and ascertainment bias in these newly described clinical entities. Some of the well characterised microdeletion syndromes and microduplication syndromes along with their clinical features are listed in Tables 1 and 2. However, it is important to remember that there might be variability in the phenotype of these conditions, depending on the size and extent of the CNV and the genes involved within the deleted or duplicated region.

 Table  1: List of some of the well-characterized microdeletion syndromes.

Chromosomal region deleted

Critical genes contributing to the phenotype, involved in the deleted region

Salient clinical features of the associated syndrome



CHROMOSOME 1p36 DELETION SYNDROME: Moderate-to-severe intellectual disability; craniofacial dysmorphism including microcephaly, deep set eyes, straight eyebrows, large anterior fontanel, pointed chin, mid-face hypoplasia, ear anomalies, and orofacial clefting; hypotonia; congenital heart disease; renal anomalies; ophthalmologic abnormalities; skeletal anomalies; hearing loss; feeding difficulties; seizures; and brain abnormalities.

1q21.1 (most often ˜200-kb deletion at chromosome band 1q21.1) in trans with a heterozygous RBM8A hypomorphic allele)


THROMBOCYTOPENIA ABSENT RADIUS (TAR) SYNDROME: Hypo-megakaryocytic thrombocytopenia that disappears with age; bilateral absent radii with presence of thumbs; other skeletal abnormalities; cardiac anomalies; genitourinary anomalies; and non-immunoglobulin E (IgE)-mediated cow’s milk allergy with gastrointestinal symptoms.


WHSCR1 (Nkx2-5, H3K36me3 specific HMT), WHSCR2

WOLF-HIRSCHHORN SYNDROME (Figure 5A): Pre- and postnatal growth restriction; microcephaly; distinctive facial features with a “Greek warrior helmet” appearance; preauricular tags & pits; cleft lip/ palate; congenital heart disease (atrial septal defect, ventricular septal defect, or pulmonic stenosis); intellectual disability; and immunodeficiency.

5p15 (the deletion may be gross or submicroscopic ranging from 0.5 Mb to up to 40 Mb in size)


CRI-DU-CHAT SYNDROME (Figure 5B): Craniofacial dysmorphism including microcephaly, round face, hypertelorism, micrognathia, epicanthal folds and low-set ears; hypotonia; severe psychomotor retardation and intellectual disability; and a characteristic high-pitched cat-like cry (especially in the newborn period).

5q35 (large deletions/ duplications including the whole NSD1 gene found in around 15-50% of patients with Sotos syndrome; sequence variants within the gene account for the rest of the cases)


SOTOS SYNDROME (Figure 5C): Overgrowth; macrocephaly; hypotonia; global development delay and intellectual disability; facial dysmorphism with a prominent forehead and a long chin; premature teeth eruption; scoliosis; large hands and feet; advanced bone age; cardiac anomalies including patent ductus arteriosus and atrial septal defect; and renal anomalies including hypoplastic kidneys and hydronephrosis.



WILLIAMS - BEUREN SYNDROME (Figure 5D): Low birth weight; feeding problems; hypotonia; cardiovascular system abnormality especially supravalvular aortic stenosis (75%), peripheral pulmonary stenosis, elastin arteriopathy, hypertension and mitral valve prolapse; distinctive facial dysmorphism (formerly referred to as ‘elfin facies’) with periorbital fullness, thick lips, short nose with broad nasal tip, and large ear lobes; short stature; hoarseness of voice; overfriendliness; renal and urinary tract anomalies; hypercalcemia and/ or hypercalciuria with nephrocalcinosis; and mild to severe intellectual disability with difficulty in visuospatial tasks.



TRICHORHINOPHALANGEAL SYNDROME II/ LANGER-GIEDION SYNDROME (Figure 5E): Distinctive facial features including a large nose with a broad ridge and tip and underdeveloped alae, long philtrum, and large prominent ears; intellectual disability, ectodermal abnormalities of the skin, hair, teeth, sweat glands, and nails; skeletal abnormalities including short stature, brachydactyly, radial or ulnar deviation of fingers, coxa vara, cone shaped epiphysis, secondary joint degeneration, joint space narrowing, and subchondral sclerosis; and multiple exostoses/ osteochondromas.



WILMS TUMOUR-ANIRIDIA- GENITOURINARY ANOMALIES- MENTAL RETARDATION (WAGR) SYNDROME: Aniridia and other associated eye anomalies such as iris hypoplasia, congenital cataract, and glaucoma; Wilms tumour by the age of 4 years in up to 90% of affected children; genital abnormalities including hypospadias, bicornuate uterus and streak ovaries; intellectual disability; behavioural abnormalities; hypotonia; epilepsy; corpus callosal agenesis; and obesity.



JACOBSEN SYNDROME (Figure 5F): Thrombocytopenia; cardiac defects; recurrent infections; craniofacial dysmorphism including microcephaly, trigonocephaly, low-set ears, epicanthal folds, hypertelorism, abnormal eyebrows and eyelashes, short nose with upturned tip, large carp-shaped mouth and micrognathia; ocular abnormalities such as eyelid/iris/ chorioretinal coloboma, strabismus, microcornea, microphthalmia; structural renal defects; intellectual disability; gastrointestinal anomalies; brachydactyly and fifth digit clinodactyly; failure to thrive


Maternal copy deletion (Around 70% of patients with Angelman syndrome have this deletion)


ANGELMAN SYNDROME: Intellectual disability; severe speech impairment; ataxic gait; tremors of limbs; inappropriate happy demeanour like frequent laughing smiling and excitability; seizures; and microcephaly.


Paternal copy deletion (Around 70-75% of patients with Prader-Willi syndrome have this deletion)


PRADER-WILLI SYNDROME (Figure 5G): Infantile hypotonia; feeding problems; failure to thrive in infancy followed by excessive weight gain /obesity; hyperphagia; mild facial dysmorphism including almond-shaped and up-slanting eyes; hypogonadism with small penis and cryptorchidism and pubertal delay; developmental /intellectual delay; sleep apnoea; short stature; hypopigmentation; and small hands.

16p13.3 (Around 50-60% of Rubinstein-Taybi syndrome are associated with the CREBBP gene, of which around 20% are due to large deletions involving one or more exons or the whole gene).


RUBINSTEIN-TAYBI SYNDROME (Figure 5H): Prenatal and postnatal growth restriction; microcephaly; dysmorphic facies including high-arched eyebrows, overhanging columella, down-slanting palpebral fissures and a grimacing smile; broad thumbs and halluces; intellectual disability; congenital heart disease; and eye abnormalities including glaucoma, cataracts, and strabismus.



MILLER-DIEKER SYNDROME: Lissencephaly; growth restriction and failure to thrive; facial dysmorphic features including a prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw; severe psychomotor retardation; opisthotonos; and seizures.



SMITH-MAGENIS SYNDROME (Figure 5I): Feeding problems and hypotonia in infancy; craniofacial dysmorphism with brachycephaly, mid-face retrusion, deep-set eyes, broad and square-shaped face, broad nose, relative prognathism and downturned upper lip; developmental delay; intellectual disability; sleep abnormalities; EEG abnormalities; and stereotypic and self-injurious behaviour.

20p12 (Around 10% of Alagille syndrome patients have a large deletion encompassing multiple exons of JAG1 or the whole JAG1 gene; the rest have either sequence variants in the JAG1 gene (around 88%) or in the NOTCH2 gene (around 2-3%)


ALAGILLE SYNDROME (Figure 5J): Paucity of intrahepatic bile ducts with chronic cholestasis; cardiac anomalies; butterfly vertebrae; posterior embryotoxon of the eye; and dysmorphic facies including triangular facies, broad forehead, deep-set eyes, large ears and a long nose with a bulbous tip.



PHELAN-MCDERMID SYNDROME: Neonatal hypotonia; global developmental delay; moderate to profound intellectual disability; facial dysmorphism; large fleshy hands; dysplastic toenails; decreased perspiration/pain; behavioural anomalies such as mouthing or chewing non-food items; and autism.



DIGEORGE SYNDROME (Figure 5K): Congenital heart disease particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus); palatal abnormalities including velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate; craniofacial dysmorphism including hooded eyelids, ear anomalies, prominent nasal bridge, bulbous nose, micrognathia, asymmetric crying facies and craniosynostosis; learning difficulties; immune deficiency with variable T cell deficiency and recurrent infections; autoimmune disorders such as idiopathic thrombocytopenic purpura; hypocalcemia and parathyroid abnormalities; and thymic hypoplasia.



CONTIGUOUS Xp22 DELETION SYNDROME: developmental delay; autistic features; Kallmann syndrome with anosmia and hypogonadotropic hypogonadism; X-linked ichthyosis; ocular albinism; brachytelephalangic chondrodysplasia punctata and short stature; and epilepsy in some patients


 Figure 5: Clinical photographs of patients with some of the common microdeletion and microduplication syndromes. The typical dysmorphic features listed in Tables 1 and 2 are seen in these patients. A. Wolf-Hirschhorn syndrome (chromosome 4p16.3 deletion) - ‘Greek warrior helmet’ appearance B. Cri-du-chat syndrome (chromosome 5p deletion) - round facies and epicanthal folds C. Sotos syndrome – macrocephaly, large forehead and prominent chin. D. Williams- Beuren syndrome (chromosome 7q11.23 deletion) - periorbital fullness, short nose, broad nasal tip, malar flattening, long philtrum, and wide mouth. E. Trichorhinophalangeal syndrome II (chromosome 8q24.1 deletion) - large nose with a broad ridge and tip, and sparse eyebrows. F. Jacobsen syndrome - microcephaly, ocular hypertelorism, epicanthal folds, strabismus, depressed nasal bridge, low set ears, and short neck G. 17 years-old boy with Prader-Willi syndrome (chromosome 15q11-q13 deletion) - short stature, obesity and delayed secondary sexual development. H. Child with Rubinstein-Taybi syndrome (i) facial dysmorphism including downslanting palpebral fissures, ‘grimace-like’ smile, and overhanging columella. (ii) broad and radially deviated thumbs (this clinical photograph courtesy Professor Shubha Phadke, Department of Medical Genetics, SGPGIMS, Lucknow) I. Smith-Magenis syndrome (chromosome 17p11.2 deletion) - mid-face retrusion, deep-set eyes, broad nose, relative prognathism and downturned upper lip J. Alagille syndrome - triangular facies, broad forehead, deep-set eyes with icterus, and a long nose with a bulbous tip. K. DiGeorge syndrome (chromosome 22q11.2 - a prominent nasal bridge, bulbous nose, micrognathia and (inset) cleft palate. L. Beckwith-Wiedemann syndrome – mildly coarse facies with macroglossia M. Potocki-Lupski syndrome - ocular hypertelorism, smooth

 Table  2: List of some of the well-characterized microduplication syndromes.

Chromosomal region duplicated

Critical genes contributing to the phenotype, involved in the duplicated region

Salient clinical features of the associated syndrome



Macrocephaly; mild intellectual disabilities; attention deficit- hyperactivity disorder. Incomplete penetrance and variable expressivity are seen.



Microcephaly; low-set, simple ears; downturned corners of the mouth; long, bushy eyebrows; long eyelashes; high nasal bridge; eye abnormalities (microphthalmia, cataracts, iris colobomas); mild to moderate intellectual disability, cleft palate; and renal and cardiac anomalies.



(Sotos critical region)

Microcephaly; global developmental delay; short stature; growth retardation; delayed bone age; and seizures in some patients.


Williams-Beuren critical region

Hypotonia; developmental delay and autism spectrum disorders; dysmorphic features are mild and without a clear characteristic pattern; brain abnormalities and seizures reported in some patients.


Paternal copy duplication


BECKWITH-WIEDEMANN SYNDROME (Figure 5L): Macrosomia; macroglossia; omphalocele; prominent eyes; ear creases; large kidneys; hyperplasia of pancreas; and hemihypertrophy.



(Angelman/Prader-Willi critical region)

Hypotonia; global developmental delay; autism spectrum disorder; ataxia; and seizures.


No definite genes implicated

Neuropsychiatric disorders


No definite genes implicated

Mild intellectual disability; facial dysmorphism including receding anterior hairline, broad medial eyebrows, hypertelorism, epicanthal folds, downslanting palpebral fissures, broad nasal base and high nasal bridge, and full lower lip; joint laxity and in some cases contractures; and hypospadias and other genital anomalies in males.



(Rubinstein-Taybi critical region)

Normal growth; mild to moderate developmental delay; small and proximally implanted thumbs; long fingers, and mild arthrogryposis with camptodactyly; facial dysmorphic features include deep-set eyes, narrow palpebral fissures, wide nasal bridge, long philtrum, and thin upper lip; cardiac defects (atrial septal defect, tetralogy of Fallot), submucous cleft palate anomalies, and eye anomalies (strabismus, blepharophimosis, and ptosis). Incomplete penetrance is reported.


No definite genes implicated

Behavioral abnormalities; cognitive impairment; autism; congenital heart defects; and skeletal manifestations such as hypermobility, craniosynostosis, and polydactyly.


No definite genes implicated

Variable clinical presentations ranging from normal in most cases to developmental delay; autistic spectrum disorders; behavioural issues; and thoracolumbar syringomyelia.


Miller-Dieker critical region

Developmental delay; central nervous system anomalies; and autism spectrum disorder.



CHARCOT-MARIE-TOOTH DISEASE TYPE 1A – demyelinating hereditary motor-sensory neuropathy (HMSN) resulting in progressive distal neuromuscular weakness with pain, weakness, deformity, and paresthesias, foot drop, pes cavus, and distal muscle wasting.

(Deletion of this gene is associated with hereditary neuropathy with liability to pressure palsy)



(Smith-Magenis critical region)

POTOCKI-LUPSKI SYNDROME (Figure 5M): Neurobehavioral abnormalities and autism; facial dysmorphism may be mild/ non-specific and includes micrognathia, hypertelorism, downslanting eyes, and large mouth.



Variable clinical features that range from normal cognition to severe intellectual disability, hypotonia, and joint laxity.



Mild to severe intellectual disability (deficits of memory performance, perceptual organization, and verbal comprehension, attention deficit and hyperactivity, and speech impairment); growth restriction; velopharyngeal incompetence; heart defects; palatal abnormalities; visual and hearing impairment; seizures; microcephaly; ptosis; and urogenital abnormalities. Intra and interfamilial variability present.



Infantile hypotonia; mild to moderate developmental delay; microcephaly; autism spectrum disorder; growth deficiency; and mild dysmorphic facial features.



MECP2 DUPLICATION SYNDROME: Neurodevelopmental disorder with hypotonia; severe intellectual disability and developmental delay; recurrent respiratory infections; seizures; progressive spasticity with involuntary spasms; and feeding difficulty, hypotonia and failure to thrive in the neonatal period.

5 Diagnostic Evaluation

Thorough clinical evaluation including a detailed history, family history with three-generation pedigree, dysmorphology evaluation and systemic examination, along with the relevant ancillary imaging studies and laboratory investigations are essential prerequisites for the diagnostic evaluation.

If a specific MMS is suspected clinically, targeted genetic evaluation for the same can be done through testing methods which use locus-specific probes such as the fluorescence in situ hybridisation (FISH) technique or the more cost-effective multiplex ligation-dependent probe amplification (MLPA) technique.

If, however, a definite syndrome is not identifiable clinically, a broad-spectrum test such as chromosomal microarray (CMA), which can detect CNVs throughout the genome, is preferred. In fact, genome-wide copy number variation assessment through CMA is recommended as the first-tier approach for evaluation of any patient presenting with unexplained global development delay, intellectual disability, multiple malformations and/or autism spectrum disorder, by the American College of Medical Genetics and Genomics (ACMG) (Riggs et al., 2020). CMA is also recommended in the prenatal setting when fetal structural anomalies (not fitting into the pattern of any specific identifiable monogenic condition) are diagnosed by prenatal ultrasound or following stillbirth, and also when either parent is a carrier of a balanced chromosomal rearrangement. Whole genome sequencing (WGS), even with low coverage (‘low pass’ with average 5X coverage), is emerging as a better modality for detection of CNVs, as it can detect the chromosomal breakpoints down to the single nucleotide level (Dong et al., 2016; Uguen et al., 2020). However, the main challenge with these high throughput tests is the interpretation of all the genomic data.

To aid in the interpretation of such large genomic data, interactive web-based databases that contain information about apparently normal controls and diseased individuals are available. Examples of these databases include the Database of Genomic Variants (DGV; http://dgv.tcag.ca/dgv/), a ‘population database’ which contains information on 980,000 CNVs and over 4,000 inversions that are not disease-causing and identified in the normal population. Absence of the CNV in a population database like DGV is an indicator that it may be pathogenic. This has to be confirmed by checking databases like DECIPHER (DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources; https://decipher.sanger.ac.uk/) and ISCA (International Standards for Cytogenomics Array Consortium; http://www.iscaconsortium.org/consortium-data/), which list the known pathogenic CNVs, with the corresponding reported phenotypes. It is also important to search published literature for previously reported information about the CNVs. The standards for interpretation, analysis and reporting of CNVs in the clinical setting have been outlined by ACMG and the Clinical Genome Resource (ClinGen) (Riggs et al., 2020).

The molecular techniques available for detecting MMS along with their advantages and limitations, are listed in Table 3.

 Table  3: Genetic testing methods for diagnostic evaluation of microdeletion and microduplication syndromes.







A combination of multiple oligonucleotide arrays and SNPs spanning the entire genome is used. The test DNA is made to hybridise onto these probes fixed on a microarray chip and the signals emitted based on the relative hybridization are read and analysed. Can be used to detect CNVs more than 10-100 kb in size, across the genome (Figure 6A).

A fluorescently-labelled probe (approximately 50 to 200 kilobase in size) complementary to a specific genome region is used for each FISH reaction. The probe hybridizes to the corresponding genomic region on the slide and the emitted fluorescence produces ‘signals’ which are detected through fluorescence microscopy. A single probe or a combination of a few probes can be used at a time.

The probe set contains around 40-50 pairs of probes. Each pair of probes of unique length hybridise to a specific sequence of DNA, following which ligation and amplification is done. The amplified products are separated through capillary electrophoresis based on their size and the relative peak size is measured, to detect the CNV (Figure 6B).

The entire genome is sequenced through the massively parallel next generation sequencing technology and computational analysis of the data is done. Both SNVs and CNVs can be detected with this method.

Preferred for

Genome-wide detection of any CNV; particularly useful for unexplained intellectual disability and multiple malformation syndromes, when no specific diagnosis is identified clinically.

Confirmation of a specific microdeletion or microduplication syndrome detected clinically

Detection of common microdeletion or microduplication syndrome which is clinically suspected; MLPA probe sets for common microdeletions, subtelomeric regions etc. are available commercially, with which a group of well characterised CNVs can be evaluated together.

Non-specific genome wide analysis of both SNVs and CNVs


  • Comprehensive genome-wide analysis of CNVs
  • SNP arrays can detect uniparental disomy
  • Can be automated

  • Balanced chromosomal aberration in a parent (leading to unbalanced situations in the index patient), low-level mosaicism and complex rearrangements in a patient can also be detected
  • Analysis of interphase nuclei in addition to metaphase spreads

  • A single reaction allows simultaneous hybridization of multiple probes designed to include multiple microdeletion and microduplication syndromes
  • Simple and quick test, doesn’t involve complex analysis

  • Both CNVs and SNVs detected simultaneously
  • Can identify the breakpoints accurately down to the last nucleotide
  • Can detect even balanced chromosomal rearrangements
  • Can be automated


  • Cannot detect low-level mosaicism and complex rearrangement
  • Likelihood of detecting CNVs of unknown significance, which are difficult to interpret

  • Targeted testing which requires prior clinical identification
  • Duplications are harder to verify

  • Targeted testing which requires prior clinical identification
  • Cannot detect low-level mosaicism
  • Covers only limited number of loci

  • Generates a large amount of data which requires a great deal of expertise to analyse.
  • Detects a huge number of variants of uncertain significance which can be difficult to interpret.


Less expensive than WGS, more expensive than FISH and MLPA. However, cost is declining.

Less expensive than CMA and WGS if locus specific probes are available.

Relatively cheap

Very expensive; costs are declining

Turnaround time

2-3 weeks; involves interpretation of data that is time consuming

Reported within 24-72 hours

Within 24-48 hours

6-8 weeks; data analysis is time-consuming.

CMA – Chromosomal microarray
FISH – Fluorescence in situ hybridization
MLPA – Multiplex ligation-dependent probe amplification
WGS – Whole genome sequencing
SNP – Single nucleotide polymorphism
CNV – Copy number variation
SNV – Single nucleotide variant


6 Genetic Counseling

In order to provide accurate genetic counseling, the diagnosis of a definite MMS has to be confirmed through one of the above-mentioned testing methods. If a CNV other than the ones associated with known microdeletion-microduplication syndromes is detected, its pathogenicity has to be ascertained as outlined above. Based on the diagnosis, counselling is provided regarding symptomatic and supportive care as well as surveillance for anticipated complications. In view of multisystem involvement, multidisciplinary management is usually required. Most of the microdeletion and microduplication syndromes follow an autosomal dominant pattern of inheritance. If the parents of an affected child are clinically normal, the chromosomal aberration would have arisen de novo in the proband, in majority of the cases. However, because of the possibility of low-level or germline mosaicism for the pathogenic chromosomal CNV in one of the asymptomatic parents, there might be an up to 1% risk of recurrence in their subsequent offspring. Less commonly, the CNV in the proband may result from a balanced chromosomal rearrangement in a parent, in which case the risk of recurrence in subsequent offspring of the couple could be as high as 30 - 50%, depending on the nature of the rearrangement (Ranganath et al., 2011). Parental origin is more likely if the proband is found to have two CNVs (especially one microdeletion and one microduplication) involving two different segments of the same or different chromosomes; in such a scenario, it is very important to do karyotyping of both parents to look for a chromosomal rearrangement such as an inversion or a translocation. Reduced penetrance and variable expressivity for some of the CNVs further complicate the counseling process, making it difficult to predict the phenotype in the sibling or offspring of an individual with such a CNV.

7 Conclusion

Microdeletion and microduplication syndromes are frequently associated with intellectual disability, multiple congenital anomalies, autistic spectrum disorders and other phenotypic abnormalities. Recent advances in molecular cytogenetic testing techniques have led to the discovery of several new microdeletion and microduplication syndromes. Some of these syndromes are identifiable based on consistent, clinically recognizable features; however, for many of them clinical diagnosis may be difficult due to variability in expression and/or non-specificity of the phenotype. For some CNVs, variable expressivity and reduced penetrance have complicated the establishment of their clinical significance. Currently, the ‘genotype-first’ approach is used to first delineate the region of deletion or duplication prior to matching the clinical presentation, leading to a growing list of these syndromes. In addition to existing techniques of FISH, MLPA and CMA, WGS is emerging as an important technique for diagnosing MMS.


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