Analysis of a Chinese pedigree with autosomal dominant Charcot-Marie-Tooth disease type 2A2A / 中华医学遗传学杂志

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.

Analysis of NF1 gene variants among thirteen patients with neurofibromatosis type 1 / 中华医学遗传学杂志

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.

Clinical and genetic analysis of a case with infantile Parkinsonism with motor delay due to tyrosine hydroxylase deficiency / 中华医学遗传学杂志

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.

Clinical and genetic diagnosis of a pedigree affected with autosomal recessive Alport syndrome / 中华医学遗传学杂志

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.

Clinical characteristics and genetic analysis of primary coenzyme Q10 deficiency caused by COQ4 gene mutation / 中华内分泌代谢杂志

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.

Clinical and genetic diagnosis of a pedigree affected with autosomal recessive Alport syndrome / 中华医学遗传学杂志

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.

Clinical characteristics and genetic analysis of primary coenzyme Q10 deficiency caused by COQ4 gene mutation / 中华内分泌代谢杂志

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 of 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 repoted. 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.