Pangenia Genomics provides the genetic testing of FHSD1 based on the Molecular Combing and Genomic Morse Code technology. This method uses specific fluorescent probes to hybridize with genomic DNA molecules (extracted from fresh blood samples) linearly stretched on coverslips. The fluorescent signals can then be visualized to distinguish the length (number of D4Z4 repeat units) and the type (haplotype A or B) of the D4Z4 loci. Most affected individuals have fewer than 10 repeats and the 4qA allele.Learn More
Pangenia Genomics offers deletion/duplication analysis to accurately detect the number of copies of the DMD gene, i.e. find out if the gene or part of the gene is deleted or duplicated. It can be used for carrier screening as well.Learn More
Pangenia Genomics offers deletion/duplication analysis in order to accurately detect deletions and duplications in the SMN1 gene. It can be used for carrier screening as well.Learn More
Pangenia Genomics offers an in vitro diagnostic (IVD) test for the detection of deletions or duplications in the PMP22, MPZ and GJB1 genes for the diagnosis of Charcot-Marie-Tooth disease type 1 (CMT1) disease. The test can be used to confirm the cause and diagnosis for hereditary neuropathy with liability to pressure palsies (HNPP) as well.Learn More
Facioscapulohumeral muscular dystrophy, or FSHD, is a genetic disorder affecting the skeletal muscles. It typically starts in the early adolescence with the weakness of muscles in the face (facio), shoulders (scapula), upper arms (humerus), and legs. Weakness is slowly progressive and can spread to any muscle. Severity is highly variable among individuals. Approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened. FSHD is estimated to affect between 4 and 10 individuals per 100,000 people.
FSHD is caused by the abnormal expression of the DUX4 gene, located in the D4Z4 region near the end of chromosome 4 at the 4q35 location. Normally, the DNA in the D4Z4 region includes 11-100 repeated segments of DNA and is hypermethylated, repressing the expression of the DUX4 gene. In FSHD, the expression of DUX4 is reactivated, with two underlying genetic mechanisms.
FSHD2 is clinically identical to FSHD1 but genetically different. In FSHD2, the length of the D4Z4 repeat array on chromosome 4q35 is in normal range. Around 80% of FSHD2 individuals carry a heterozygous mutation in the SMCHD1 gene, and some FSHD2 individuals have mutations in the DNMT3B gene. These mutations are associated with the hypomethylation and relaxation of chromatin in the D4Z4 repeat arrays on both chromosome 4q35 and 10q26. In combination with the 4qA allele, DUX4 is expressed from the D4Z4 repeat array on chromosome 4q35, leading to FSHD. FSHD2 is inherited in a digenic manner.
FSHD may be diagnosed through a thorough clinical examination, identification of characteristic physical findings, a complete individual and family history, and genetic testing (Figure 2). It usually starts with the testing of FHSD1, which accounts for 95% of the FSHD cases. For many years, the genetic testing of FSHD1 used Southern blot, which is labour and time-intensive, and just provides an estimate of the number of D4Z4 repeats. Pangenia Genomics is the first in Hong Kong to provide the genetic test of FHSD1 based on the Molecular Combing and Genomic Morse Code technology developed by Genomic Vision (http://www.genomicvision.com/products/genetic-tests/fshd/). This method uses specific fluorescent probes to hybridize with genomic DNA molecules (extracted from fresh blood samples) linearly stretched on coverslips (Figure 3). The fluorescent signals can then be visualized to distinguish the length (number of D4Z4 repeat units) and the type (haplotype A or B) of the D4Z4 loci (Figure 4). Most affected individuals have fewer than 10 repeats and the 4qA allele.Genetic testing for mutations in the SMCHD1 and DNMT3B gene may be indicated if the D4Z4 region on chromosome 4 is not contracted.
Figure 4: Examples of hybridization signals
Currently there is no treatment for FSHD, but several therapies are under investigation. Genetic treatments such as RNAi treatment to silence DUX4 have been evaluated in preclinical studies, though no human trials are currently underway. Losmapimod has been shown in preclinical studies to reduce DUX4 expression, and Phase II trials are currently enrolling for FSHD. Another FSHD treatment candidate GBC0905 is in preclinical studies (https://myocea.com/fshd).
Dystrophinopathies are diseases that are caused due to mutation in the dystrophin-coding gene, including Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD). They are one of the most common neuromuscular diseases in Hong Kong. According to a local study, the prevalence of dystrophinopathies (including DMD and BMD) in Hong Kong is around 1.03 per 10 000 males. The global prevalence is 7.1 per 100,000 males.DMD is one of the most severe types of muscular dystrophies. It is an early onset disease which causes progressive muscle degeneration. Patients start to have symptoms since childhood.
DMD and BMD are inherited diseases that can be passed on to the next generation through carriers of the defective gene. As they are X-linked recessive diseases, two copies of the defective gene (located on the X-chromosome) are required for the disease to develop. Therefore, mainly males are affected. Female cases of DMD patients are rare but they can be carriers of the defective gene and have a 50% chance of passing on the defective gene to their children.
DMD is caused by mutations in the DMD gene, which encodes the dystrophin protein. The most common mutations include large deletions and large duplications. Other mutations include point mutations and insertions.DMD can be tested by numerous methods, including blood tests, muscle biopsy, CGH-array, multiplex PCR, direct sequencing, and deletion/duplication analysis. Pangenia Genomics offers deletion/duplication analysis accurately detect the number of copies of the DMD gene, i.e. find out if the gene or part of the gene is deleted or duplicated. It can be used for carrier screening as well.
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder. It affects the survival motor neuron 1 gene (SMN1) which encodes the SMN protein. Around 95% of affected patients have deletion of exon 7 in both copies of the gene. Other mutations include point mutations. Prevalence of SMA is around 1 in 6,000 – 10,000 live births.There is an SMN2 gene which is highly similar to SMN1, differing by a nucleotide in exon 7. Due to the difference, SMN2 has lower efficiency than SMN1, hence can produce small amounts of SMN protein but cannot fully replace SMN1. The SMN2 gene can reflect the severity of the disease in SMA patients since different people have different numbers of SMN2 copies.
SMA is an autosomal recessive disorder. If an individual has two defective genes, they will be affected by SMA. If an individual only has 1 defective gene, they are carriers. If a parent is a carrier, they have 50% chance of passing the defective gene to their children. If both parents are carriers, they have 25% chance of having a child affected with SMA.
SMA is divided into types based on the age of onset and the severity of symptoms:
It is important to get a diagnosis as early as possible in order to start proper management of the condition. Tests include muscle biopsy, EMG tests and genetic testing. Pangenia Genomics offers deletion/duplication analysis in order to accurately detect deletions and duplications in the SMN1 gene. It can be used for carrier screening as well.
Treatment can help slow progression of disease and may increase lifespan.
Charcot-Marie-Tooth (CMT) disease is a group of disorders in which the motor and/or sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, as well as sensory loss. CMT is the most common form of inherited peripheral neuropathies. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. Specific gene mutations are responsible for the abnormal function of the peripheral nerves. Prevalence of CMT and related disorders has been estimated to be between 1:2500 and 1:1214.
Clinical symptoms of CMT include distal muscle weakness and atrophy, sensory loss, depressed tendon reflexes and high-arched feet (pes cavus). These manifestations occur first in the distal legs and later in the hands. At present, more than 80 genes are known to be associated with different types of CMT.
More than 80 genes are known to be associated with different types of CMT. CMT diseases can be inherited in an autosomal dominant, autosomal recessive or X-linked manner.
CMT type 1 (CMT1) is a slowly demyelinating peripheral neuropathy and several subtypes exist. CMT1A accounts for approximately 70-80% of all CMT1 cases, which is mainly caused by an approximately 1.5 Mb duplication on chromosome 17p, including the peripheral myelin protein 22 (PMP22) gene and the flanking regions. In addition to duplication, CMT1A can be caused by point mutations in the gene PMP22 as well.
Increased PMP22 gene dosage leads to altered nerve conduction velocity, which is the main cause of the clinical manifestations in CMT1A.
Another subtype of CMT disease is hereditary neuropathy with liability to pressure palsies (HNPP) and PMP22 is the only gene known to be associated with HNPP which is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop. A deletion of chromosome 17p12 that includes PMP22 is present in approximately 80% of affected individuals and the remaining 20% are due to pathogenic variant in PMP22.
CMT type 1B accounts for approximately 10-12% of all CMT1 cases and is caused by defects in the myelin protein-zero (MPZ) gene which is important in formation and stabilization of peripheral nerve myelin and interacts with PMP22. Defects in the MPZ gene cause hypertrophy of Schwann cells and mutations in MPZ can lead to polyneuropathies, Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy. CMT1A and 1B are difficult to distinguish clinically and classification is based solely on molecular testing.
X-linked CMT (CMTX) accounts for approximately 10-15% of all CMT cases and the main subtype CMTX1 is caused by defects in the Gap Junction Beta-1 (GJB1, also known as connexin-32) gene. Pathogenic variants in the GJB1 coding region account for ~90% of CMTX1.
What Pangenia Genomics offering is an in vitro diagnostic (IVD) test for the detection of deletions or duplications in the PMP22, MPZ and GJB1 genes for the diagnosis of Charcot-Marie-Tooth disease type 1 (CMT1) disease. The test can be used to confirm the cause and diagnosis for hereditary neuropathy with liability to pressure palsies (HNPP) as well.
|Other Rare Neuromuscular Disorders|
|Cardiomyopathy, dilated, 1X||Muscular dystrophy, limb-girdle, type 2E||Muscular dystrophy-dystroglycanopathy, type C5|
|Carnitine palmitoyltransferase II deficiency||Muscular dystrophy, limb-girdle, type 2F||Myasthenic syndrome, congenital, 1B, fast-channel|
|Carnitine palmitoyltransferase II deficiency, lethal neonaltal||Muscular dystrophy, limb-girdle, type 2H||Myasthenic syndrome, congenital, 1B, fast-channel|
|Carnitine palmitoyltransferase II deficiency, myopathic, stress-induced||Muscular dystrophy-dystroglycanopathy type A3||Myasthenic syndrome, congenital, 3C, acetylcholine receptor deficiency|
|Emery-Dreifuss muscular dystrophy 1||Muscular dystrophy-dystroglycanopathy type B3||Myopathy due to myoadenylate deaminase deficiency|
|Glycogen storage disease ll||Muscular dystrophy-dystroglycanopathy type C3||Myopathy, congenital, with fiber-type disproportion|
|Limb-girdle muscular dystrophy, type 2B||Muscular dystrophy-dystroglycanopathy, type A1||Myotubular myopathy|
|Miyoshi muscular dystrophy 1||Muscular dystrophy-dystroglycanopathy, type A4||Nemaline myopathy 2|
|Multiple pterygium syndrome, lethal type||Muscular dystrophy-dystroglycanopathy, type A5||Nemaline myopathy 3, congenital|
|Muscular dystrophy, Becker type||Muscular dystrophy-dystroglycanopathy, type B1||Nonaka myopathy|
|Muscular dystrophy, Duchenne type||Muscular dystrophy-dystroglycanopathy, type B4||Spinal muscular atrophy 1|
|Muscular dystrophy, limb-girdle, type 2A||Muscular dystrophy-dystroglycanopathy, type B5||Spinal muscular atrophy 2|
|Muscular dystrophy, limb-girdle, type 2C||Muscular dystrophy-dystroglycanopathy, type C1||Spinal muscular atrophy 3|
|Muscular dystrophy, limb-girdle, type 2D||Muscular dystrophy-dystroglycanopathy, type C4||Spinal muscular atrophy 4|