Clinical and genetic analysis of a child with X-linked hypohidrotic ectodermal dysplasia / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a child with X-linked hypohidrotic ectodermal dysplasia (XLHED).@*METHODS@#Clinical data of the child was collected. Peripheral blood samples were taken from the child and his parents with informed consent and subjected to copy number variation (CNV) analysis and whole exome sequencing (WES).@*RESULTS@#The male infant manifested sparse hair, anhidrosis, anuresis due to polycystic kidney dysplasia, external genital malformation and anal atresia. WES has revealed a 406 bp hemizygous deletion at Xq13 (68 836 147-68 836 553) in the proband, which encompassed exon 1 of the EDA gene. A heterozygous deletion at the same site was detected in the mother, while no deletion or duplication of the site was detected in the father.@*CONCLUSION@#The hemizygous deletion of EDA gene exon 1 probably underlay the ectodermal dysplasia in the proband. Above result has provided a basis for genetic counseling and prenatal diagnosis for the family.

Analysis of ASXL3 gene variant in a child with Bainbridge-Ropers syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child affected with Bainbridge-Ropers syndrome.@*METHODS@#Genomic DNA was extracted from peripheral venous blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out to detect genetic variant of the proband. Candidate variant was verified by Sanger sequencing.@*RESULTS@#The 3-year-old boy presented with psychomotor retardation, linguistic difficulties, mental retardation and peculiar craniofacial phenotype. A de novo heterozygous nonsense variant of the ASXL3 gene, c.3106C>T, was identified by WES in the proband, and the same mutation was not found among his parents. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.3106C>T variant was predicted to be pathogenic (PVS1+PS2+PP4).@*CONCLUSION@#The heterozygous variant c.3106C>T of the ASXL3 gene probably underlies the Bainbridge-Ropers syndrome in the patient. Above result has enabled the clinical diagnosis and genetic counseling for the family.

Phenotype and genetic analysis of three patients with PKHD1 associated autosomal recessive polycystic kidney disease at childhood, teenage and advanced age / 中华医学遗传学杂志

Objective@#The phenotype and genetics of three patients with autosomal recessive polycystic kidney disease (ARPKD) at childhood, teenage and advanced age were analyzed.@*Methods@#Next generation sequencing (NGS) was applied to all the probands. PCR and Sanger sequencing were used to verify the suspicious gene variants screened by NGS in the probands and their family members, and one of the family got prenatal diagnosis.@*Results@#Through NGS, PCR and Sanger sequencing, the 5-yr proband in pedigree 1 was shown to carry compound heterozygous variants of c. 5935G>A(p.G1979R) and c. 5428G>T(p.E1810X) of PKHD1, originated from his parents; In pedigree 2, the 17-ys proband was detected with c. 5512T>C(p.Y1838H) and c. 5935G>A(p.G1979R) variants of PKHD1 orginated from her parents, and her mother also got prenatal diagnosis during the second trimester; In pedigree 3, the 70-ys female proband was found with variants c. 11314C>T (p.R3772X) and c. 3860T>G (p.V1287G) of PKHD1.@*Conclusion@#The three pedigrees were diagnosed as ARPKD caused by PKHD1 variants. Five types of variants were detected, c. 5935G>A and c. 11314C>T were the known pathogenic variants, while c. 5512T>C, c. 5428G>T and c. 3860T>G were not reported previously. Considering the complexity of the genetics and phenotypes of the cystic renal diseases, genetic diagnosis is crucial to give accurate etiological diagnosis, which may benefit the clinic management.

A family of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy / 中华神经科杂志

Objective@#To investigate the clinical features, imaging features, pathological features and gene diagnosis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).@*Methods@#Clinical manifestations, signs and imaging characteristics of a female patient hospitalized in the First Affiliated Hospital of Zhengzhou University for more than 10 days due to headache were analyzed, and skin biopsy and HTRA1 and Notch3 gene detection were performed. The pedigree of the proband was investigated in detail, and HTRA1 gene test and related imaging examination were conducted in parallel. Due to the deceased parents of the patient, relevant genetic testing could not be conducted. A control group of 100 healthy people were analyzed.@*Results@#The clinical manifestations of proband were headache after insomnia, hearing loss in the right ear, easy to wake up and sweat at night. Brain MRI showed diffuse patchy long T1 and long T2 signals in bilateral fronto-parietal temporal occipital insula, internal and external capsule areas, bilateral basal ganglia areas, and bilateral thalamus. Fluid attenuated inversion recovery sequence showed high signals. Magnetic sensitive weighted imaging showed scattered patchy low signals in bilateral cerebral and cerebellar hemispheres, bilateral basal ganglia area, left thalamus and brain stem. The proband had consanguineous parents. A homozygous mutation C to T transition at position 589 (c.589C>T) was found in exon 3 of HTRA1 gene with the proband and both siblings. The heterozygous c.589C>T mutation appeared in another sister of the proband. Under the light microscope of skin biopsy, pigmentation in the basal layer of the skin could be seen, collagen fiber hyperplasia in the dermis was accompanied by a small amount of inflammatory cell infiltration, and no definite amyloidosis was found. No mutations were found in Notch3 gene. Because the patient′s parents were deceased, genetic testing was not possible. One hundred healthy controls had no such mutation.@*Conclusions@#The CARASIL family with HTRA1 gene c.589C>T homozygous mutation was reported, and the pathogenicity of the mutation was confirmed. HTRA1 genetic testing is recommended for diagnosis and differential diagnosis of CARASIL with family history or clinical suspicion.

A family of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy / 中华神经科杂志

Objective To investigate the clinical features, imaging features, pathological features and gene diagnosis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Methods Clinical manifestations, signs and imaging characteristics of a female patient hospitalized in the First Affiliated Hospital of Zhengzhou University for more than 10 days due to headache were analyzed, and skin biopsy and HTRA1 and Notch3 gene detection were performed. The pedigree of the proband was investigated in detail, and HTRA1 gene test and related imaging examination were conducted in parallel. Due to the deceased parents of the patient, relevant genetic testing could not be conducted. A control group of 100 healthy people were analyzed. Results The clinical manifestations of proband were headache after insomnia, hearing loss in the right ear, easy to wake up and sweat at night. Brain MRI showed diffuse patchy long T1 and long T2 signals in bilateral fronto?parietal temporal occipital insula, internal and external capsule areas, bilateral basal ganglia areas, and bilateral thalamus. Fluid attenuated inversion recovery sequence showed high signals. Magnetic sensitive weighted imaging showed scattered patchy low signals in bilateral cerebral and cerebellar hemispheres, bilateral basal ganglia area, left thalamus and brain stem. The proband had consanguineous parents. A homozygous mutation C to T transition at position 589 (c.589C>T) was found in exon 3 of HTRA1 gene with the proband and both siblings. The heterozygous c.589C>T mutation appeared in another sister of the proband. Under the light microscope of skin biopsy, pigmentation in the basal layer of the skin could be seen, collagen fiber hyperplasia in the dermis was accompanied by a small amount of inflammatory cell infiltration, and no definite amyloidosis was found. No mutations were found in Notch3 gene. Because the patient′s parents were deceased, genetic testing was not possible. One hundred healthy controls had no such mutation. Conclusions The CARASIL family with HTRA1 gene c.589C>T homozygous mutation was reported, and the pathogenicity of the mutation was confirmed. HTRA1 genetic testing is recommended for diagnosis and differential diagnosis of CARASIL with family history or clinical suspicion.

Phenotype and genetic analysis of three patients with PKHD1 associated autosomal recessive polycystic kidney disease at childhood, teenage and advanced age / 中华医学遗传学杂志

OBJECTIVE@#The phenotype and genetics of three patients with autosomal recessive polycystic kidney disease (ARPKD) at childhood, teenage and advanced age were analyzed.@*METHODS@#Next generation sequencing (NGS) was applied to all the probands. PCR and Sanger sequencing were used to verify the suspicious gene variants screened by NGS in the probands and their family members, and one of the family got prenatal diagnosis.@*RESULTS@#Through NGS, PCR and Sanger sequencing, the 5-yr proband in pedigree 1 was shown to carry compound heterozygous variants of c.5935G>A(p.G1979R) and c.5428G>T(p.E1810X) of PKHD1, originated from his parents; In pedigree 2, the 17-ys proband was detected with c.5512T>C(p.Y1838H) and c.5935G>A(p.G1979R) variants of PKHD1 orginated from her parents, and her mother also got prenatal diagnosis during the second trimester; In pedigree 3, the 70-ys female proband was found with variants c.11314C>T (p.R3772X) and c.3860T>G (p.V1287G) of PKHD1.@*CONCLUSION@#The three pedigrees were diagnosed as ARPKD caused by PKHD1 variants. Five types of variants were detected, c.5935G>A and c.11314C>T were the known pathogenic variants, while c.5512T>C, c.5428G>T and c.3860T>G were not reported previously. Considering the complexity of the genetics and phenotypes of the cystic renal diseases, genetic diagnosis is crucial to give accurate etiological diagnosis, which may benefit the clinic management.

Identification of pathogenic mutation in a Chinese pedigree affected with split hand/split foot malformation / 中华医学遗传学杂志

OBJECTIVE@#To detect potential mutation in a Chinese pedigree affected with split hand/split foot malformation (SHFM).@*METHODS@#The patients were screened for genome-wide copy number variations with single nucleotide polymorphism (SNP) microarray. Copy number variations were verified by real-time fluorescence quantitative PCR.@*RESULTS@#There were 3 SHFM patients from three generations, which conformed to an autosomal dominant inheritance. SNP microarray assay revealed that all patients have carried a 0.34 Mb duplication in 10q24.31-q24.32 (102 993 649-103 333 271) encompassing the BTRC and DPCD genes. The result was verified by real-time fluorescence quantitative PCR, confirming that the duplication has co-segregated with the SHFM phenotype in the pedigree.@*CONCLUSION@#The 10q24.31-q24.32 duplication probably underlies the pathogenesis of SHFM in this pedigree. Tiny copy number variations can result in diseases featuring autosomal dominant inheritance.