A combination of two mutations, including one that had never been reported, were found in two Chinese siblings who developed a severe form of cystic fibrosis (CF), according to a case report.
The report, “Identification of a Mutation in the Novel Compound Heterozygous CFTR in a Chinese Family with Cystic Fibrosis,” was published in the Canadian Respiratory Journal.
CF is one of the most common recessive disorders in people of Northern European descent — a recessive disorder means that patients must carry mutations in both copies of the affected gene (one from the mother and the other from the father), in this case the CFTR gene resulting in a defective or absent CFTR protein.
However, CF is much rarer in the Chinese population and is often caused by different CFTR mutations than those described in European and American patients. Only a few dozen cases of the disorder have been described in Chinese people.
In addition, while about 90% of Europeans and Americans with the disease carry at least one copy of the F508del mutation in the CFTR gene, this mutation is uncommon in Chinese patients, also suggesting that the mutations causing CF in those of Chinese descent are different from those in Western patients.
This also makes it harder to diagnose Chinese patients, since established CF screening platforms look for mutations that are common in those of European descent.
Researchers at Tianjin University in China reported the case of two siblings with typical characteristics of the disease, who carried two different mutations in their CFTR gene copies, one of which had not been previously reported.
The patients were a 33-year-old man and his 22-year-old sister. The man had an intermittent cough for the past 20 years, a history of nasal polyps for the past 10 years, and had been coughing up yellow mucus since he was young. He had also been diagnosed with bronchiectasis.
The patient was admitted to the hospital complaining of fever and wheezing for the previous month. On examination, the patient had moist rales (crackles with gurgling sounds due to fluid in the airways), finger clubbing (enlargement of the fingertips), as well as signs of respiratory failure and bronchiectasis, with Pseudomonas aeruginosa infection. His lung function was also severely low.
The man also had congenital bilateral absence of the vas deferens, a condition in which the tubes carrying sperm out of the testes do not develop normally. This disorder is seen in at least 97% of males with CF and causes infertility, though sperm can usually be retrieved using in vitro fertilization. The patient had used this method and was a father to a set of twins.
His sister was also admitted to the hospital due to a cough and coughing up mucus for the past three years that had gotten worse in the previous week. The woman also had history of nasal polyp surgery, and her examination showed bronchiectasis with P. aeruginosa infection and sinusitis.
Both siblings had much higher chloride levels in their upper limbs than normal — all levels were above 140 millimoles/L, well above the 60 mmol/L threshold for normal levels in a sweat test.
The two patients and their family underwent genetic sequencing analysis to identify the CFTR mutations causing the disease. Both siblings had the same mutations — called c.3484 C > T and c.400 A > G — the latter of which had not previously been reported to cause CF.
The c.3484 C > T mutation caused the nucleotide (the building blocks of DNA) thymidine to replace a cytidine in position 3484 of the DNA sequence, which resulted in a smaller protein and relatively severe clinical signs.
The other mutation was a substitution of the nucleotide adenosine for a guanine in position 400. While its effect is unclear, the researchers believe that it worsens the effects of the c.3484 C > T mutation, since the patients’ father and the twins carried this mutation with no signs of disease. The c.3484 C > T mutation was inherited from the patients’ mother.
Given the difference in CFTR mutations between Caucasians in Western countries and Chinese patients, the team advocates for the establishment of a CFTR mutation database for the Asian population to help in understanding the different symptoms in these patients.
“The variant spectrum in the Chinese population is different from that of the Western population; thus, a CFTR mutation database for the Asian population is greatly needed,” the researchers concluded.
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