1. Clinical and genetic diagnosis of a pedigree affected with autosomal recessive Alport syndrome
Lili GE ; Chongfen CHEN ; Lei LIU ; Yinsen SONG
Chinese Journal of Medical Genetics 2019;36(9):914-917
Objective:
To explore the genetic basis of a child with chronic kidney disease featuring renal shrinkage and creatinine increase.
Methods:
Peripheral venous blood samples were taken from the child, his brother and two parents and subjected to whole exome sequencing. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the structure and function of the protein product.
Results:
High-throughput and Sanger sequencing revealed that the child has carried compound heterozygous mutations of the COL4A4 gene, namely c. 4550T>G in exon 47 (inherited from his mother) and c. 199C>T in exon 5 (inherited from his father). Neither mutation was reported previously. Bioinformatic analysis showed that both mutations have located in highly conserved regions. The same mutations were not found in his brother.
Conclusion
The compound heterozygous c. 4550T>G and c. 199C>T mutations probably underlie the disease in this child. The findings have enriched the mutation spectrum of the COL4A4 gene.
2.Analysis of a Chinese pedigree with autosomal dominant Charcot-Marie-Tooth disease type 2A2A.
Ding ZHAO ; Rui LI ; Bojie ZHAO ; Jinghui KONG ; Chongfen CHEN ; Jijun SONG
Chinese Journal of Medical Genetics 2021;38(2):181-183
OBJECTIVE:
To explore the genetic basis of a pedigree affected with peroneal muscular atrophy.
METHODS:
Neuroelectrophysiological examination and whole exome sequencing were carried out for the proband, a six-year-and-ten-month-old boy. Suspected variant was verified in his family members through Sanger sequencing. Bioinformatic analysis was carried to predict the conservation of amino acid sequence and impact of the variant on the protein structure and function.
RESULTS:
Electrophysiological examination showed demyelination and axonal changes of motor and sensory nerve fibers. A heterozygous missense c.1066A>G (p. Thr356Ala) variant was found in exon 11 of the MFN2 gene in the proband and his mother, but not in his sister and father. Bioinformatic analysis using PolyPhen-2 and Mutation Taster software predicted the variant to be pathogenic, and that the sequence of variation site was highly conserved among various species. Based no the American College of Medical Genetics and Genomics standards and guidelines, the c.1066A>G (p. Thr356Ala) variant of MFN2 gene was predicted to be likely pathogenic (PS1+ PM2+ PP3+ PP4).
CONCLUSION
The heterozygous missense c.1066A>G (p.Thr356Ala) variant of the MFN2 gene probably underlay the disease in the proband, and the results have enabled genetic counseling and prenatal diagnosis for this family.
Charcot-Marie-Tooth Disease/genetics*
;
Child
;
China
;
Drosophila Proteins/genetics*
;
Exons
;
Female
;
Heterozygote
;
Humans
;
Male
;
Membrane Proteins/genetics*
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Mutation
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Pedigree
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Pregnancy
;
Whole Exome Sequencing
3. Clinical characteristics and genetic analysis of primary coenzyme Q10 deficiency caused by COQ4 gene mutation
Lili GE ; Chongfen CHEN ; Lei LIU ; Xuan ZHENG ; Jinghui KONG ; Yinsen SONG
Chinese Journal of Endocrinology and Metabolism 2019;35(12):1014-1018
Objective:
To explore the clinical and genetic characteristics of primary coenzyme Q10 deficiency caused by coenzyme Q4 (COQ4) variants.
Methods:
Clinical data were collected, while COQ4 gene was sequenced.
Results:
Here were reported a boy of 3 months old who came to our hospital presented with feeding difficulties, repeated respiratory infections, convulsions for 3 months. He was subsequently diagnosed as cerebral atrophy, and growth retardation. All exons were sequenced.c.211G>A(p.A71T, maternal), c. 436T>A(p.F146I, paternal) were detected. After treatment with coenzyme Q10, the convulsive symptoms improved significantly. Literature review revealed that totally 14 cases with primary coenzyme Q10 deficiency caused by COQ4 gene mutation were reported. The onset age varies from neonatal to 18 years old, and the clinical manifestations are heterogeneous, including cardiomyopathy, epilepsy, ataxia, cerebellar atrophy, respiratory insufficiency, and growth retardation.
Conclusion
For cases with atypical clinical manifestations of primary coenzyme Q10 deficiency, gene detection is helpful for an early diagnosis and treatment.
4.Clinical and genetic diagnosis of a pedigree affected with autosomal recessive Alport syndrome.
Lili GE ; Chongfen CHEN ; Lei LIU ; Yinsen SONG
Chinese Journal of Medical Genetics 2019;36(9):914-917
OBJECTIVE:
To explore the genetic basis of a child with chronic kidney disease featuring renal shrinkage and creatinine increase.
METHODS:
Peripheral venous blood samples were taken from the child, his brother and two parents and subjected to whole exome sequencing. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the structure and function of the protein product.
RESULTS:
High-throughput and Sanger sequencing revealed that the child has carried compound heterozygous mutations of the COL4A4 gene, namely c.4550T>G in exon 47 (inherited from his mother) and c.199C>T in exon 5 (inherited from his father). Neither mutation was reported previously. Bioinformatic analysis showed that both mutations have located in highly conserved regions. The same mutations were not found in his brother.
CONCLUSION
The compound heterozygous c.4550T>G and c.199C>T mutations probably underlie the disease in this child. The findings have enriched the mutation spectrum of the COL4A4 gene.
Child
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Collagen Type IV
;
genetics
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Exons
;
Female
;
Humans
;
Male
;
Mutation
;
Nephritis, Hereditary
;
diagnosis
;
genetics
;
Pedigree
;
Whole Exome Sequencing
5.Clinical and genetic analysis of a case with infantile Parkinsonism with motor delay due to tyrosine hydroxylase deficiency.
Chongfen CHEN ; Jinghui KONG ; Lili GE ; Lei LIU ; Yinsen SONG
Chinese Journal of Medical Genetics 2020;37(4):455-458
OBJECTIVE:
To explore the clinical characteristics and genetic variants in a child with tyrosine hydroxylase-deficient infantile Parkinsonism with motor delay.
METHODS:
Clinical feature of the patient was summarized. Genomic DNA was extracted from peripheral blood samples taken from the child and her family members. All exons of GCH1, TH and SPR genes were subjected to targeted capture and next-generation sequencing. Suspected variants were verified by Sanger sequencing.
RESULTS:
The child could not sit alone at 7 month and 11 days. Physical examination suggested motor retardation and hypotonia, limb stiffness, head nodding, slight torticollis, and language and intellectual developmental delays. She developed involuntary shaking of limbs at 3 month old, which lasted approximately 10 seconds and aggregated with excitement and before sleeping. Cranial MRI revealed widening of subarachnoid space on the temporomandibular and particularly temporal sides. Genetic testing revealed that she has carried a nonsense c.457C>T (p.R153X) variant, which was known to be pathogenic, and a novel missense c.720C>G (p.I240M) variant of the TH gene. The two variants were derived from her father and mother, respectively.
CONCLUSION
The child was diagnosed as tyrosine hydroxylase-deficient infantile Parkinsonism with motor delay due to compound heterozygous variants of the TH gene. Above finding has enriched the spectrum of TH gene variants.
Brain
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diagnostic imaging
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Codon, Nonsense
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Dystonic Disorders
;
congenital
;
genetics
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Female
;
Genetic Testing
;
High-Throughput Nucleotide Sequencing
;
Humans
;
Infant
;
Magnetic Resonance Imaging
;
Mutation
;
Parkinsonian Disorders
;
genetics
;
Tyrosine 3-Monooxygenase
;
genetics
6.Analysis of NF1 gene variants among thirteen patients with neurofibromatosis type 1.
Lili GE ; Yaodong ZHANG ; Lei LIU ; Xuan ZHENG ; Chongfen CHEN ; Jinghui KONG
Chinese Journal of Medical Genetics 2021;38(9):829-832
OBJECTIVE:
To detect variants of NF1 gene among thirteen patients with neurofibromatosis type 1.
METHODS:
Genomic DNA was extracted from peripheral blood samples of the patients. High-throughput sequencing was employed to detect potential variants of the NF1 and NF2 genes.
RESULTS:
Thirteen pathogenic variants were identified among the patients, which included one NF1 deletion, three missense variants, three nonsense variants and six frameshifting variants. Among these, 10 variants have been associated with neurofibromatosis type 1. c.4180A>T (p.Asn1394Tyr), c.4217dupT (p.Leu1406fs) and c.1753dupT(p.Leu585Phefs*3) were unreported previously. Based on the guidelines of the American College of Medical Genetics and Genomics, c.4180A>T (p.Asn1394Tyr) was predicted to be likely pathogenic (PS2+PM1+PM2+PP2), while c.4217dupT (p.Leu1406fs) and c.1753dupT (p.Leu585Phefs*3) were predicted to be pathogenic (PVS1+PS2+PM2).
CONCLUSION
Variants of the NF1 gene probably underlay the disease among these children. Above findings have enriched the the spectrum of NF1 gene variants.
Child
;
Genes, Neurofibromatosis 1
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Genomics
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High-Throughput Nucleotide Sequencing
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Humans
;
Mutation
;
Neurofibromatosis 1/genetics*
7.Analysis of clinical phenotypes and MMACHC gene variants in 65 children with Methylmalonic acidemia and homocysteinemia.
Chongfen CHEN ; Yaodong ZHANG ; Lili GE ; Lei LIU ; Xiaoman ZHANG ; Shiyue MEI ; Shuying LUO
Chinese Journal of Medical Genetics 2023;40(9):1086-1092
OBJECTIVE:
To carry out Sanger sequencing for MMACHC gene variants among 65 Chinese pedigrees affected with combined methylmalonic aciduria and homocysteinemia, and summarize their genetic and clinical characteristics and prognosis.
METHODS:
Clinical characteristics of the 65 children identified with Methylmalonic acidemia and homocysteinemia at the Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital) from April 2017 to April 2022 were selected as the study subjects. Potential variants of the MMACHC gene were detected by direct sequencing of the PCR products.
RESULTS:
The median age of the 65 children was 3 months (14 days to 17 years old). These included 28 cases (43.08%) from neonatal screening, 11 cases (16.92%) with a history of jaundice, and 9 cases (13.85%) with various degrees of anemia. The main clinical symptoms included development delay, slow growth, epilepsy, hydrocephalus, lethargy, feeding difficulty, regression or decline in motor ability, recurrent respiratory infections, anemia, jaundice, respiratory and heart failures, hydrocephalus, limb weakness, and hypertension. Blood and urine tandem mass spectrometry screening has revealed increase of methylmalonic acid, propionyl carnitine, propionyl carnitine/acetylcarnitine ratio, and propionyl carnitine/free carnitine ratio to various extents, and blood homocysteine was increased in all patients. The detection rate of genetic variants was 98.46% (128/130), and in total 22 types of MMACHC gene variants were detected. The most common ones have included c.609G>A (W203X) (58/128), c.658-660del (K220del) (19/128), and c.80A>G (Q27A) (16/128). Two novel variants have been identified, namely c.565C>T (p.R189C) and c.624_ 625delTG (p.A208Afs), which were respectively predicted as likely pathogenic (PM2_Supporting+PM3+PP2+PP3) and pathogenic (PVS1+PM2_Supporting+PM3+PP2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Exon 4 had the highest frequency for the detection.
CONCLUSION
Identification of MMACHC gene variants has confirmed the diagnosis in the children, among which the c.609G>A variant has the highest frequency. Discovery of the new variants has enriched the mutational spectrum of the MMACHC gene.
Humans
;
Amino Acid Metabolism, Inborn Errors/genetics*
;
Hydrocephalus
;
Oxidoreductases