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Year : 2016  |  Volume : 5  |  Issue : 3  |  Page : 105-117

An overview of rare genetic disorders and recent diagnostic approaches

Genetics Laboratory, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chennai, Tamil Nadu, India

Date of Web Publication14-Dec-2016

Correspondence Address:
V Ramakrishnan
Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Health City, Kelambakkam - 603 103, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2278-0521.195812

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Genetic disorders are the leading causes of mortality and morbidity in humans. The prevalence of genetic diseases varies widely between different clusters depending on their organization, reproductive practices, and various other sociocultural factors. These disorders are mainly caused by mutations in monogenic, polygenic or the combination of gene mutations, consanguineous marriage practices, and environmental factors leading to damage of chromosomes. Nearly 7000 different types of rare genetic diseases/disorders are being discovered frequently. Cytogenetic and molecular techniques have been widely implicated to detect variations in the chromosomes and in genes. Several innovative and extremely robust methods for sequencing the nucleic acids such as next-generation sequencing have become available in the past few years for diagnosing chromosomal and genetic disorders. We have summarized the rare genetic disorders, their cytogenetic location, candidate genes, novel mutations identified, and advanced diagnostic tools that are currently being used for rapid detection of these abnormalities. The application of advanced technologies is rapidly changing the background of genetic research and also in clinical practice. The identification of novel disease-causing genes, mutations, and predisposing genetic variants data is getting into accelerated. The availability of huge genetic information will uphold a better indulgent of genetic disease etiology, permit early, even per-symptomatic diagnosis, and preventive measures to avoid the onset of the disease. This review will make clinicians/pediatricians to classify rare disorders with their genes responsible, leading for accurate genetic diagnosis.

Keywords: Cytogenetics, diagnosis, exons, genetic diseases, mutation

How to cite this article:
Ramakrishnan V, Akram Husain R S, Kumar S G. An overview of rare genetic disorders and recent diagnostic approaches. Saudi J Health Sci 2016;5:105-17

How to cite this URL:
Ramakrishnan V, Akram Husain R S, Kumar S G. An overview of rare genetic disorders and recent diagnostic approaches. Saudi J Health Sci [serial online] 2016 [cited 2023 Mar 22];5:105-17. Available from: https://www.saudijhealthsci.org/text.asp?2016/5/3/105/195812

  Introduction Top

Genetic disorders are primarily caused by certain abnormalities observed in several genes. It could be categorized into four major types such as single gene, multi-factorial, chromosomal, and mitochondrial disorders. Heredity plays a vital role in almost all kinds of the disorders, recent advances in genomic research have shown a gradual increase of candidate genes and their genetic risk factors leading to a variety of medical complications. To date, there are 7000 of known genetic diseases are identified in humans. These abnormalities result from a mutation of particular gene which are commonly termed as hereditary disorders/diseases and also demonstrate distinct patterns of inheritance from the affected families. [1] The diseases which are inherited occur due to genetic imbalance or mutations transferred from the parent to their offspring during the time of conception.

Almost sixty identifiable syndromes have been linked with rare abnormalities in the chromosome. They are commonly observed in <5% in the newborns, 6% of stillbirths, and 5% of couples with multiple miscarriages and in 50% of spontaneous abortions. [Figure 1] explains the worldwide mortality rate of children less than five years of age. These data have been retrieved from the WHO, levels and trends in child mortality 2015, UNICEF. [2] In women aged >35 years, the chromosomal anomalies are being reported up to 2% of all pregnancies. Every year 4 million babies were born approximately; nearly 3%-4% were born with genetic disorders or major defects during the birth, and 1% of babies will be born with abnormalities in their chromosome, in turn causing physical problems such as mental illness. Then, >20% of juvenile deaths are caused by their genetic makeup or defects during birth (e.g, abnormalities of the nervous system, congenital heart defects, and chromosomal anomalies). [3]
Figure 1: World map showing mortality rate of children (under age 5). The underage fi ve mortality rate of children's worldwide. It has been retrieved from the WHO, levels and trends in child mortality 2015, UNICEF

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Nearly 30% of children and 10% of the adults admitted in hospitals are due to genetic diseases. [4] A third cluster of anomalies exists where genetic and environmental risk factors interrelate in producing a disease. Cardiovascular malformations are vital class of birth defects and posses' difficult challenges, threats to cardiologists with the prevalence being reported to be 1.5 cases/1000 live births. [5] In addition to consanguineous marriages, the repetition risks for an undiagnosed multiple malformation syndromes are expected to be very high. The incidence of consanguinity reported in India is 5-60% where the first cousin and uncle-niece are the more frequently occurring relationships in Indian population. [6]

Rare chromosome disorders carry missing, rearranged, extrachromosomal material, but they exclude common chromosome conditions such as Turners, Down syndrome. They are complex to identify as they occur in lower frequency. Then, 1/200 babies were born with a rare chromosomal anomalies, many of them have symptoms from their birth or in early childhood, and the remaining get diagnosed when they have repeated miscarriages, stillbirths, and also with fertility problems. [7] Genetic counseling is also recommended for the parent awareness, knowledge of disorders occurring after birth. In this review, attempts have been made to explain the rare chromosomal disorders and the novel mutations identified in their candidate genes which might be useful for researchers, clinicians, and cytogenetic professionals. Genetic disorders are caused by abnormalities in the nucleic acids contained within our cells while most of them are heritable and some are sporadic. These disorders are multifactorial and caused by several mutations, environmental factors. Here, we have summarized some of the rare genetic disorders and their candidate genes and their reported mutations. [Table 1] provides the list of disorders, their chromosomal locations, prevalence/incidence rate, mode of inheritance, gene responsible, total exons, and its amino acids. [8] The burden of rare genetic diseases [9],[10],[11],[12],[13] and their diagnostic barriers is illustrated in [Figure 2] and [Figure 3].
Figure 2: The burden of rare genetic diseases

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Figure 3: The diagnostic barriers in rare genetic disorders

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Table 1: List of disorders and their responsible genes.

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  Genetic Disorders Top

Alstrom syndrome

This is an atypical autosomal recessively inherited disorder categorized by features such as cone rod dystrophy, sensorineural hearing loss, hyperinsulinemia, hypogonadism, and finally leading to multiple organ dysfunctions. The Alstrom syndrome 1 (ALMS1) gene observed on chromosome at position 2p13.1, spanning 23 exons, encoding a protein of 4169 amino acids, and Alstrom syndrome (AS) is caused by several mutations in ALMSI gene. [14] The estimated prevalence rate for AS is 1-9/1,000,000 individuals with almost 700 cases reported worldwide. Patients suffering from AS carried a familial reciprocal translocation of chromosome observed in: 46-XY, t(2;11)(p13;q21) have been reported. [15],[16]

The dysfunction of the primary cilia caused by mutations in gene ALMS1 leads to AS. Pathogenic variations in this gene have been widely reported in various ethnic populations and exons 08, 10, and 16 are the hotspot regions in ALSM1 gene. [17] A total of 79 mutations have been reported in the ALMS1 gene, which include 55 novel mutations, among 250 individuals with a clinical diagnosis of AS. [18] In Japanese patients, whole-exome sequencing (WES) has been used to screen for variations in ALSM1 gene which identified a novel mutation (c.6151C>T in exon 8), causing a premature termination codon at amino acid p.Q2051X. Exome sequencing approach is very useful in detecting pathogenic mutations observed in the candidate genes. [19] Globally, 40% and 70%-80% mutations in Northern Europe region are detected in ALSM1 gene through molecular genetic testing. A study published in the year 2015 in patients with clinical symptoms of AS in a global cohort of 204 families revealed 109 novel mutations in the ALSM1 gene using next-generation sequencing (NGS), highlighting the allelic heterogeneity in AS. [20]

Batten disease

It is commonly known as Juvenile Batten disease or Juvenile neuronal ceroid lipofuscinosis. They inherit in autosomal recessive pattern leading to neurodegenerative disease of onset in children between 5 and 10 years. The symptoms associated with this disease include cognitive decline, seizures, vision loss, movement disorders, and retinopathy. This disease has estimated incidence range from 7/100,000 births worldwide. [21] They are caused by mutations in the ceroid-lipofuscinosis-3 (CLN-3) gene located in chromosome 16 at position p.12.1 containing 17 exons with protein coding 438 amino acids. [22] This gene is coded by a protein termed as CLN3 or battenin; they are found in the cell membranes such as lysosomes and endosomes. CLN3 mutations are the important risk factors for Juvenile NCL. Prenatal diagnosis (PND) is available for Batten disease in the families where mutations in CLN3 gene are already known. [23] A study comprising 11 patients from Australia of different age group affected by neuronal ceroid lipofuscinosis showed mutations such as c.560T>C, c.184C>T, c.662A>G, c.200T>C, c.308G>A, c.712T>A, and c.713T>C in CLN6 gene all had functional effects. [24]

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome

This is an auto-inflammatory disorder which is inherited in an autosomal recessive pattern. Recent reports identify that mutations in PSMB8 gene may be as the causative factor of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). The PSMB8 gene is located on chromosome no 6 at position p21.32 spanning 6 exons coding for protein containing 276 amino acids. [25] This gene is responsible for encoding over 20 components that constitute the proteasomes in the cells. In patients with CANDLE syndrome, the PSMB8 mutation causes protein waste products to get accumulated leading to malfunction of the proteasomes in cells all over the body. [26] Homozygous missense mutation has been identified c.224C>T (p.Thr75Met) in the PSMB8 gene of patients with this syndrome. [27] A novel nonsense mutation has been reported in PSMB8 gene (c.405C>A) of CS patient and previously reported mutations were also identified in patients of US origin. [25] Likewise in five patients with CS, three harbored homozygous mutations and two patients had heterozygous mutations in PSMB8 gene; in addition, those patients had higher levels of gamma-interferon-induced protein-10. [28] A 3-year-old boy of Caucasian ethnic background was born to consanguineous parents affected by CANDLE syndrome at 11 months of age and screened for mutations in PSMB8 gene which revealed homozygous c.280G>C, p.A94P novel mutation. [29]

Ehlers-Danlos syndrome

This is a heritable type of disorder in the connective tissue categorized by fragile, skin hyperextensibility, atrophic scars, soft skin, and also joint hypermobility. The prevalence of Ehlers-Danlos syndrome (EDS) is estimated as 1:20,000. [30] EDS is caused by mutations leading to a nonfunctional COL5A1 (allele) and resulting to Type V collagen deficiency. [31] It is located on chromosome no 9 at position q34.3. Above 1000 mutations have been observed in the COL1A1 and COL1A2 genes and they are reported in OI mutation database, majority of these mutations exist in the triple helix domain of pro-collagen Type I gene. [32] EDS was reported in 42-year-old German and when analyzed for mutation in COL5A1 gene which showed de novo heterozygous nonsense mutation, but no variations have been reported in COL3A1 gene. [33] De novo heterozygous deletion of 13.7-Mb was observed in chromosome at 2q23.3-q31.2 in EDS phenotype thereby leading to deletion of the COL3A1, myostatin, and COL5A2 genes. [34] In Belgium, 126 patients diagnosed with classic EDS were screened for mutations in COL5A1, A2 genes which showed 73 patients harboring COL5A1 mutations and 13 with COL5A2 mutations. [35] Heterozygous mutations were observed such as 4-bp deletion of intronic region which led to deletion (234-bp) of exon (65) in the processed mRNA in EDS I COL5A1-linked families. [36]

Fatal familial insomnia

Fatal familial insomnia (FFI) are described as rare human prion disease which is autosomal dominant in pattern, clinically characterized by a progressive untreatable insomnia, motor signs, and dysautonomia. [37] The mutations occurring in the PRioN Protein (PRNP) gene are responsible for this disease. PRNP is a protein coding gene located in chromosome 20 at position p13 coding 02 exons and contains 73 amino acids. The function of PRNP protein is to transport copper into cells and to protect the injury of neurons. They play a major role in formation of synapses. The missense mutation observed in 178 and 129 codon (methionine-valine) polymorphism in PRNP gene is a risk factor of the disease. [38] Variations have been reported in Japanese family affected by FFI with mother and son harboring met129val, D178N homozygous mutations. [39] The same mutation has been observed in a French patient genetically confirmed with this disease and also reported with pseudo-hypersomnia behavior. [40] Similar mutations were observed in Chinese patient affected with FFI carrying aspartic acid to asparagine (178), Met 129 genotype in the PRNP gene, showing clinical symptoms such as progressive dementia together with behavioral disturbances. [41]

Fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is an atypical sporadic disorder inherited as autosomal dominant where the muscle and connective tissue such as ligaments, tendons are slowly getting replaced by bone forming in the outer surface of the skeleton (heterotopic bone) finally the movement gets constrained. [42] The activin A receptor, type I (ACVR1) gene, has been associated with this disease. This gene is observed in chromosome no 2 at position q24.1 containing 11 exons. The ACVR1 protein is observed in tissues such as the cartilage and in the skeletal muscle. Report suggests that mutations observed in the ACRV1 gene change the receptor shape during certain situations and disrupt the mechanisms controlling the activity of receptors. [43]

Genome-wide linkage analysis was conducted in 5 families affected with FOP identified linkage to chromosome 2q23-q24 including the ACVR1 gene. [44] A de novo R206H mutation was observed in ACVR1 gene in 3-year-old girl of Taiwanese origin having clinical symptoms of progressive heterotopic ossificans and first metatarsal bones. [45] The same mutation was also reported in 3 Japanese patients having sporadic FOP and represents that R206H is frequent in patients worldwide. [46] Heterozygous mutation (R202I) was observed in the ACVR1 gene of a 20-year-old woman showing clinical symptoms of FOP. [47] Likewise, a 22-year-old adult of Japanese origin harbored heterozygous mutation (L196P) in ACVR1 with delayed onset and mild course of FOP. [48]

Hereditary angioedema

This disorder is caused by deficiency of complement component 1 (C1) and esterase inhibitor (Cl-INH). It occurs in autosomal dominant pattern. There are three types of hereditary angioedema (HAE) such as Type I, II and III, in which the common is Type I (85%). [49] The disease incidence is 1 in 50,000 live births and C1-INH (SERPING1) gene mutations are responsible for this disease. The cytogenetic location of this disease is 11q12.1 spanning 8 exons with protein containing 500 amino acids. Most of the HAE is familial and nearly 300 known genetic mutations were observed in this gene caused by dysfunctional C1 inhibitor. [50] Advance genomic techniques can be used in detecting the changes in other genes responsible for this disease. A nonsense mutation has been reported in CINH gene with patients affected by Type I hereditary angioedema. [51] A study on 87 Spanish families clinically proven to be with HAE identified 10 insertions/micro-deletions, 13 large rearrangements, 10 missense, 8 splicing, and 5 nonsense mutations in the C1NH gene. [52] Recent study published in 2016 from Jordan comprising 14 cases with C1-INH-HAE clinical symptoms documented mutations in SERPING1 gene such as c.203C>T (p.Thr46Ile) located in N-terminal domain of the C1-inhibitor protein and the other c.800C>T (p.Ala245Val) influencing the phenotype. [53] Similar study published in Brazil screened coding regions of SERPING1 gene from thirty cases with clinically proven HAE, which identified fifteen different mutations. It comprised five small deletions and seven missense mutations such as c.752T>C, c.550G>C, c.498C>A, c.889G>A, c.1376C>A, c.1431C>A, and c.1396C>T and one nonsense mutation c. 1480C>T having functional role in C1-INH. [54]

Hutchinson-Gilford progeria

This is much fatal premature genetic disease categorized under the progeroid syndromes. The average incidence is 1/8 million live births with symptoms such as early aging among children, finally leading to death at an early age. This occurs in autosomal dominant condition. [55] The mutations observed in the LMNA gene are responsible for this disease and the cytogenetic location is 1q22 containing 12 exons coding for lamin-A protein with 664 amino acids. This syndrome occurs because of an uncontrolled production of the protein the lamin-A. The frequent LMNA mutation in Progeria Syndrome is nucleotide substitution at the 1824 position C-T, G608G change thereby activating the cryptic splice site by deleting 150 nucleotides in exon 11 causing loss of function. [56] De novo point mutations have been reported in LMNA gene causing Hutchinson-Gilford progeria in the year 2003. The patients harbored de novo single-base substitution, a Cytosine to Thymine transition resulting in a silent glycine-to-glycine change at codon 608 (G608G) in the 11 th exon of LMNA gene. [57] Atypical progeroid syndromes patients were screened for variations in LMNA gene 11 th exon which harbored heterozygous mutations disturbing the splicing sites. [58]

Harlequin ichthyosis

Harlequin ichthyosis (HI) is a rare genetic disorder affecting the skin. Children's with this condition are born with very thick, hard skin covering their bodies, disease occur in recessive inheritance pattern. Their skin forms into large diamond-shaped plates splitted by deep fissures that limit movement. [59] The mutations occurring in the ABCA12 gene are causative factor for this disease. The cytogenetic location is 2q35 spanning 53 exons. The protein coded by this gene plays function in the transport of lipids in the epidermis. Deletions, insertions, and nonsense and missense mutations have been reported in the patients suffering from HI. PND is available for this disease. [60] A de novo deletion has been documented in the long arm of 18 th chromosome; the karyotype was 46-XY, deletion (18) (q21.3) a male patient suffering from HI. [61] Large intragenic and frame shift deletions were observed in 11/12 patients affected with HI Frame shift mutations were reported in Italian patient in exon 33 (5229delA) and missense mutation, D2363N in exon 45 of ABCA12 gene. [62] A study with 14 patients showing clinical features of HI, the ABCA12 gene was sequenced fully which showed 2 heterozygous mutations, 9 patients were homozygous and 3 patients harbored mutations in one allele. [63]

Krabbe disease

This is an atypical inherited metabolic neurodegenerative disease caused by the deficiency of enzyme called galactosylceramidase. This dysfunction of the gene leads to progressive loss of myelin sheath. The disease prevalence is approximately 1/100000 births with difference between countries. Mutations observed in the GALC gene are responsible for Krabbe disease (KD). [64] This gene is positioned on chromosome 14q31encoding for the B-galactocerebrosidase protein. According to the Human Gene Mutation Database reports, 128 variations have been reported in GALC gene as the causative factor of KD. [65] GALC gene mutations were screened in 17 Japanese having KD found 12del3ins and I66M + I289V accounted for 37% including 2 additional variations G270D, T652P accounted for up to 57% in Japanese patients. [66] Studies with 30 Italian patients with clinically confirmed KD have reported 33 mutations occurring in GALC gene which includes 15 novel mutations such as 7 frame shift mutations, 1 splice site change, 3 nonsense, and 4 missense mutations. [67] A recent study published in the year 2015 on 11-month-old male child of Moroccan ethnicity presenting with clinical symptoms of KD. GALC gene mutations were screened by DNA sequencing approach which revealed two novel heterozygous mutations such as c.860G>A (p.Cys287Tyr), c.1622G>A (p.Trp541) affecting GALC structure and function in turn helps to identify the associated phenotypes related with KD. [68]

Lamellar ichthyosis

This is a genodermatosis present at birth with symptoms of tight, clear sheath covering the entire skin called as collodion membrane. They inherit autosomal recessive pattern and classified as the genetically heterogeneous set of cornification diseases. [69] The major cause of lamellar ichthyosis (LI) is inactivating mutations found in the TGM1 gene. This gene is located on chromosome no 14q11.2 spanning 15 exons and encodes for Transglutaminase-1enzyme. Nearly 130 pathogenic variations have been reported in TGM1 gene associated with LI in affected patients from diverse ethnic groups. The most common variation in TGM1 gene c.788 G/A nonsense mutation have been observed in Tunisian patients and they belong to consanguineous families. [70] In Chinese patient, a novel mutation (homozygous) of adenine → cytosine transition observed in 3 rd exon (c.386 A>C) of TGM1 gene has been reported. [71] Another report from Italy in patients with LI has identified novel mutations in TGM1 gene p.R37G, p.V112A, p.W263X, p.S550X, c.851_877del, p.G473S, and c.1465_1492del responsible for the disease. [72] Prenatal genetic counseling and testing is available for LI. A study from autosomal recessive congenital ichthyosis families from Galicia with 16 patients exhibiting LI of Spanish origin were screened for mutations in TGM1 and 5 ARCI-associated genes, identified 11 probands carrying mutations in TGM1 gene. [73]

Lesch-Nyhan syndrome

They are described as X-linked recessive condition occurring exclusively in males and clinical symptoms such as neurological abnormalities and excess production of uric acid in the body, especially women are asymptomatic carriers. The estimated incidence rate of Lesch--Nyhan syndrome (LNS) is 1/100,000 live births. The hypoxanthine-guanine phospho ribosyl transferase (HGPRT) gene plays an essential role in purine nucleotides recovery. The deficiency of HGPRT enzyme leads to excess production of uric acid. This gene is located in chromosome Xq26.2 spanning 9 exons and coding for protein with 218 amino acids. Mutations observed in HGPRT gene are heterogeneous and 600 variations are reported all over the world. [74] The LNS patients carry 30% de-novo and 70% mothers remain as somatic carriers of these mutations. Prenatal genetic diagnosis can be performed as carrier detection during risk pregnancies. [75] A recent study published in the year 2015 from USA documented novel mutation in LNS family with a deletion followed by insertion such as c.428_432del and p.Met143Lys in exon 6 of HPRT1 gene which discloses the genetic heterogeneity of this gene might be responsible for HGPRT deficiency. [76]

Mowat-Wilson syndrome

The clinical symptoms of Mowat-Wilson syndrome (MWS) leads to distinctive facial features, hypertelorism, intellectual disability, mental retardation, and finally multiple congenital anomalies (MCA) which are inherited in autosomal dominant pattern. The incidence rate 1 in 70,000 live births and MWS is not diagnosed exactly due to various clinical features. [77] The zinc finger E-box-binding homeobox 2 gene (ZEB2) mutations are the risk factor for MWS. The chromosomal location is 2q22.3 containing 10 exons spanning 70 kb. Heterozygous point mutations and deletions were observed in ZEB2 gene associated with HWS. [78] Reports from Brazilian HWS patients identified mutations in exon 8, 10 of ZEB2 gene (980C>A, 2699delC, 941delA, 1118delT, 3382delG, 1027C>T, 1640C>G) using Sanger sequencing method. [79] Nearly 110 different mutations have been described in the ZEB2 gene in which 41% of them are nonsense mutations and most of them were localized mainly in 8 th exon of ZEB2 gene. [80]

Pompe disease

This disease is commonly known as glycogen storage disease Type II primarily caused by α-glucosidase (lysosomal enzyme) deficiency with symptoms leading to the accumulation of lysosomal glycogen in skeletal, smooth muscle, nervous system and also in the heart inherited in autosomal recessive pattern. [81] The incidence is approximately 1/40,000 births and GAA (glucosidase, alpha acid) gene is responsible for this disease and this gene is located on chromosome no 17 at q25.3 spanning 20 exons coding for protein with 952 amino acids. [82] To date, 400 different mutations have been described with Pompe disease (PD) and c.-32-13 T>G is the most frequent mutation observed in affected individuals (patients) belonging to Caucasian ethnic groups with high mutational frequency of 34%-47%. [83],[84] The variations observed in GAA gene were c.2238G>C and c.1935C > A which are common Taiwanese patients. [85] Reports from Chinese patients suffering from PD showed 10 novel mutations identified by DNA sequencing such as c.323G>A, c.1562A > T, c.503G>C, c.1993G>A, c.2161G>T, c.1355delC, c.1315_1317delATG, c.2431delC, c.1551 + 3_c.1551 + 6del AAGT, and c.241C>T playing major role in the disease progression. [86]

Proteus syndrome

Proteus syndrome (PS) is rare and sporadic, clinically characterized by progressive, segmental overgrowth in body parts such as skin, tissues, and bones with an incidence of <1 in 1,000,000 people worldwide. [87] PS results from the mutations occurring in the AKT1 gene located in chromosome 14q32.33 containing 15 exons with 480 amino acids coding for the protein Serine-threonine protein kinase. AKT is the one of the major component of PI3K/AKT signaling pathway which regulates the cellular processes including cell proliferation, growth and finally cell death. Mutations in AKT gene disrupts the cell's ability and allows the cells to divide abnormally. [88] Somatic mutation c.49G>A, pGlu17Lys has been shown for the mosaic overgrowth in PS. The patients diagnosed for PS have been tested for this particular mutation and all of them have shown positive. [89] A recently published study on 2016 with 38 patients clinically proven with symptoms of PS was screened for variations in AKT1 gene which revealed 3%-35% mutation levels which are correlated histopathologically. [90]

Von Hippel-Lindau syndrome

Von Hippel-Lindau syndrome (VHL) is clinically characterized by abnormal growth of tissue in several organs including pheochromocytoma, central nervous system, retinal hemangioblastoma, epididymal cystadenoma, and tumor in pancreas. [91] The incidence of this disease is estimated to be 1/36,000 individuals and inherited in autosomal dominant pattern. Mutations observed in the VHL gene are major cause of VHL syndrome. VHL gene is basically a tumor suppressor gene mapped on chromosome locus 3p25.3 spanning 03 exons, encodes for two different protein VHL such as pVHL19 and pVHL30. [92] In Chinese family novel VHL gene mutations such as R120T, H125P and 623(TTTTGTTG) have been reported and they have resulted by dysfunction of pVHL. [93] Some common germ line mutations include Argl67Trp, Leu178Pro, del Phe76, Argl61Stop, Arg167Gln, and Asn78Ser. The mutation frequency was 27% for missense mutations, 15%-20% deletions, and 27% were nonsense mutations observed in VHL gene. Another frame shift mutation 327del C observed in exon 1 of VHL gene in Chinese patient affected by VHL syndrome. [94] Analysis of VHL gene mutations was performed 49 family members of Turkish origin having clinical and genetic features of VHL syndrome. The sequence analysis revealed heterozygous p.A149S mutation in all the symptomatic patients and in 7 asymptomatic family members. [95]

All the above mentioned rare genetic disorders are being diagnosed worldwide. It is imperative to have knowledge on disease pathology, candidate genes, responsible mutations and advanced diagnostic methods available for screening which will be helpful in reducing the mortality of these abnormalities.

  Diagnostic Tools Top

Due to rapid development of technologies in the current scenario, the diagnosis of genetic disorders has become easy, fast and more precise. They have enormous impact on genetic counseling. The methods used for detection can be briefly explained as follows. Amniocentesis was used as standard invasive diagnostic procedure in pregnancy during the second trimester. The analysis of chromosomes from amniotic fluid samples is highly accurate and the risk of error is extremely little. Then it has been replaced by chorionic villus sampling which was introduced to identify in the first trimester itself. [96] The other techniques include karyotyping, Fluorescence in situ hybridization (FISH) using specific chromosomal probes, chromosomal microarray (CMA), NGS, comparative genome hybridization (CGH) and the amplification of polymorphic chromosome-specific markers by multiplex polymerase chain reaction (PCR). Advantages of these robust techniques provide karyotyping within 48-72 h of duration, using chorionic villi or aminocytes. Techniques such as karyotyping and FISH have its own impact on the results. Recent techniques have become more sensitive and accurate in identifying the specific targets. So there is in need to have better understanding of the newer methods available for diagnosis.

The most common clinical genetic tests of patients with genetic disabilities are "Microarray-based genomic copy-number analysis." They are also called as "Molecular Karyotyping" and "Chromosomal Microarray (CMA)." The CMA has been widely used to diagnose individuals suffering from autism spectrum disorders, MCA, intellectual disability/developmental delay. [97] The International Standard Cytogenomic Array Consortium has also said that CMA can be used for wider spectrum to diagnose chromosomal disorders. They have compared conventional karyotyping method with CMA. The NGS technologies are promising to be used in clinical settings for improving human health, planning for genetic diagnosis, amidst their expensive costs. The available NGS platforms are provided by Illumina, 454 Life Sciences, Helicos Biosciences, GS FLX Titanium, Pacific Biosciences, Life Technologies SOLiD4, Complete Genomics and Oxford Nanopore Technologies. [98]

Fluorescence in-situ hybridization

This technique was developed in the 1980s by a team of biomedical scientists, used to provide specific localization of genes on chromosomes; they can visualize specific cytogenetic abnormalities including deletion, translocation, and copy number aberrations. Their workflow is by hybridizing a probe (DNA) to its corresponding sequence, on the chromosomal preparations which are already precoated on slides. These probes are labeled directly or indirectly, by incorporating the reporter molecules that are consequently detected by fluorescent antibodies and finally visualized under the microscope. Rapid diagnosis of chromosomal abnormalities such as trisomies, monosomies, and microdeletions are acquired using specific probes. They can able to detect deletions ranging from 200 to 500 kb. They are performed as direct approach to the interphase nuclei or metaphase chromosomes. [99] FISH has gained recognition worldwide as a physical mapping technique and support for large-scale mapping the chromosomes related to the human genome project. Three FISH probes are used to detect the chromosomes involved in translocations and other inherited chromosome anomalies. Nearly 35 types of FISH methods are available currently for diagnosis of various disorders observed in humans, and this technique remains as Gold standard method in biomedical research. [100] Multicolor FISH (detection of chromosome copy number-24 human chromosomes) has been used for identifying mosaicism and nuclear organization from human embryonic nuclei. [101]

Comparative genomic hybridization

This is a special type of FISH technique (using dual probes), mainly used for detecting all genomic imbalances occurring in humans. This technique permits the detection of copy number changes in chromosome by-passing the need for culturing of cells. The detection size has been estimated from several experiments to be in the range from 10 to 20 Mb. The fundamentals of this technique are the total genomic DNA of the given abnormal (patient) sample with the total genomic DNA of normal cells can be compared. The normal DNA and the affected patient DNA are labelled with two different dyes that are fluorescently labeled. The final mixture is added, hybridized and observed under the fluorescence microscopy, and the results are compared with the Fluorescence ratio. [102] The methodology followed in this technique has been illustrated in [Figure 4].
Figure 4: Workfl ow for comparative genome hybridization

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There are certain limitations of this technique, as it cannot detect the structural chromosomal aberrations devoid of the copy number changes, such as inversions, balanced chromosomal translocations, and the ring chromosomes. The sensitivity of array CGH depends on size and level of the changes in the copy number. A research group from Brazil have recently identified various chromosomal anomalies in neonates using micro array-based CGH, where the disease etiology is being unidentified, especially in the neonates. [103] This technique can be used as major diagnostic tool by helping the families by providing exact diagnosis where the chromosomal anomalies are observed.

Quantitative fluorescence polymerase chain reaction

This is well established molecular genetic technique used to identify the copy number of DNA sequence by the amplification of sequence repeats in the polymorphic loci. Application for diagnostic approach was first suggested in the year 1993, followed by the development of a quantitative fluorescence-PCR (QF-PCR)-based test for detecting the imbalances in sex chromosome. The UK National Health Service has introduced QF-PCR as a validated diagnostic test in the year 2000 for identifying the chromosomal abnormalities. [104] The DNA extracted from chorionic villi or uncultured amniocytes are used as sample source, they amplify DNA markers for the chromosomes of our interest. The fluorescently labeled primers bind to specific target sequence and leads to amplification followed by capturing the fluorescent signals using computer-assisted measurement. Already markers of specific chromosome such as 13, 21, and 18 occasionally for X and Y are commercially available.

The assessment performed by UK Health Technology reports that QF-PCR is consistent and accurate as karyotype, FISH for detecting the abnormalities. [105] QF-PCR has been widely used in testing aneuploidy for cost-effective, rapid diagnosis. The advantage of QF-PCR is their automation procedure, where the clinical samples are analysed by high throughput methods at a basic cost which can be afford easily by the common people. QF-PCR will continue to play a vital role in the PND of chromosomal abnormalities in the current scenario. The usage of QF-PCR could be of great help in countries like India, China, the prenatal detection of chromosomal abnormalities by cytogenetic analyses are delayed/hindered by lack of skilled technicians; cost of the tests which cannot be afforded by the people in low- or middle-income group. [106]

Multiplex ligation-dependent probe amplification

This method works under PCR-based technology by discriminating the copy number of the required target sequences. MLPA uses custom-designed probes, where the short DNA fragments bind specifically to the target sequence (exons). They target small sequences and also distinguish those differing in a change of single nucleotide. They are fast, inexpensive and use two probes of unique length, hybridized to adjacent target sequences. Finally, using capillary electrophoresis system, the peaks are observed, and the copy number of each chromosome is determined using normalized calculations. This technique has been used effectively in several countries and in research groups for detecting aneuploidy in PND. [107] The relative copy number of all exons in a gene, deletions, and duplications in chromosomal disorders can be easily determined with high sensitivity using this technique. One advantage of MLPA over QF-PCR based method enables us to detect fifty different genomic DNA sequences in a single PCR reaction. MLPA is used to detect specific clinical variations observed in a gene which cause alterations in genes associated with inherited diseases like duchene muscular dystrophy, hereditary neuropathy with liability to pressure palsies, familial adenomatous polyposis, spinal muscular atrophy, breast cancer (BRCA1 and BRCA2), Ovarian cancer and Charcot-Marie-Thoot disease. [108]

Whole-exome sequencing

Exome sequencing with the utilization NGS technologies has been proven to be effective for gene-panel tests and locus-specific diseases in diagnostic/research setting and also for establishing the molecular mechanism of certain diseases. It is the robust technology in current scenario globally for identifying various changes caused by chromosomal anomalies. They have the capability to characterize diseases at the epigenetic, transcriptomic and at genomic levels. This approach is being used to sequence the protein-coding genes in the genome through high-throughput methods. The methodology of this technique is illustrated in [Figure 5]. WES workflows include four basic steps such as (1) Library preparation, (2) cluster generation, (3) Sequencing, (4) data analysis and interpretation of results. In the year 2014, a research group from Bengaluru, India used WES approach to detect mutations in genes such as (LTBP2, FBN1, and ADAMTS10) responsible for Weill-Marchesani syndrome and these mutations can be incorporated in the genetic testing panel of this disease in diagnostics. [109] The limitations of this technique are they can able to recognize only the variations in the protein-coding region of the gene and not in other regions.
Figure 5: Workfl ow for whole-exome sequencing

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PND has been performed using fetal DNA isolated from maternal serum by WES in identifying the aneuploidies with a noninvasive method. [96] WES was performed for 29 patients clinically proven with Proteus syndrome in which 26 DNA samples harbored somatic mutations such as p.Glu17 Lys, c.49G → A, E17K in the AKT1 gene. [110] Understanding the genetic and epigenetic patterns of the diseases leads to the identification of mutations useful for early-diagnosis, prognosis and also for therapeutic approaches. WES has been applied in various areas of diagnostics and research: In brief, including the PND, mutation detection in heterogeneous disorders, preimplementation genetic diagnosis and newborn screening procedures. WES is a cost-effective alternative approach when compared with the whole-genome sequencing.

  Conclusion Top

Chromosomal abnormalities significantly contribute to genetic disorders that have been associated with a wide range of developmental consequences together with intellectual disability, language impairments, and behavioral problems. These shared characteristics may be due to the more general effects of imbalances in chromosomes, rather than specific anomalies. This impact has been documented from different ethnic populations in the affecting the fetus or the individual directly or in making healthy offspring. Due to increase in population, high birth rate and consanguineous marriage practices lead to more prevalence of genetic disorders/chromosomal anomalies worldwide.

Preventive genetics could be achieved through accessible information provided in databases for well-known genetic disorders, premarital, preimplantation in genetic diagnosis and finally by the genetic counseling. We have made an attempt to summarize the rare genetic disorders globally and diagnostic methods available for early detection which could be useful in terms of prevention as well as the management of the disease. These genetic disorders affecting human mankind in several stages; it is imperative especially for clinicians, pediatricians, and researchers to be familiar with recent genetic testing methods as well as application of these tests in clinics and in biomedical research labs to get tailor-made diagnosis. These diseases can be prevented in the early stages or even before using the above-mentioned techniques.

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Conflicts of interest

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1]


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