Variant analysis for a pedigree affected with limb-girdle muscular dystrophy type 2D / 中华医学遗传学杂志

OBJECTIVE@#To analyze variant of SGCA gene in a Chinese pedigree affected with limb-girdle muscular dystrophy type 2D with whole exome sequencing (WGS).@*METHODS@#Multiplex ligation-dependent probe amplification (MLPA) was employed to detect large fragment deletion or duplication of the DMD gene. FastTarget next generation sequencing was used to detect variants of the DMD gene, and the result was verified by Sanger sequencing. After excluding the diagnosis of DMD for the proband, WGS was applied to test the proband and his parents. Suspected pathogenic variants were validated by Sanger sequencing.@*RESULTS@#No variant, deletion or duplication of the DMD gene was detected. Whole exome sequencing showed that the proband has carried compound heterozygous missense variants c.409G>A (p.Glu137Lys) and c.409G>C (p.Glu137Gln) in exon 5 of the SGCA gene, which were respectively inherited from his mother and father. Neither variant was found in DNA derived from the cord blood sample.@*CONCLUSION@#The c.409G>A (p.Glu137Lys) and c.409G>C (p.Glu137Gln) compound heterozygous missense variants probably underlie the disease in the proband. Above finding has facilitated genetic counseling and prenatal diagnosis for the family.

Analysis of SACS mutation in a family affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay / 中华医学遗传学杂志

OBJECTIVE@#To carry out mutation analysis for a Chinese family affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).@*METHODS@#Whole exome sequencing (WES) was used to screen potential mutations within genomic DNA extracted from the proband. Suspected mutation was validated by combining clinical data and results of Sanger sequencing.@*RESULTS@#A homozygous deletional mutation c.3665_3675delGTGCTGTCTTA (p.S1222fs) was found in the proband, for which her parents were both heterozygous carriers.@*CONCLUSION@#WES is capable of detecting mutation underlying this disorder and facilitating genetic counseling and prenatal diagnosis for the affected family. A novel pathogenic mutation of the SACS gene was discovered.

Whole exome sequencing analysis for a Chinese pedigree affected with X-Linked intellectual disability / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the clinical features and genetic mutation in a family affected with non-syndrome X-linked intellectual disability (NS-XLID) using whole exome sequencing (WES).</p><p><b>METHODS</b>Multiplex ligation-dependent probe amplification (MLPA) was applied to screen potential mutations of Fragile X syndrome (FXS). Whole exome sequencing (WES) and Sanger sequencing were screen for pathological mutations.</p><p><b>RESULTS</b>FXS was excluded by MLPA analysis. WES has discovered in the proband an ARX gene mutation c.88G>T, which was confirmed by Sanger sequencing. Combining his clinical phenotype with information from the OMIM database, it was inferred that the ARX mutation probably underlies the NS-XLID in the proband. The same mutation was found in his mother and two uncles but not in his father and sister.</p><p><b>CONCLUSION</b>WES is capable of revealing the mutation underlying NS-XLID and can facilitate genetic counseling for the affected families.</p>

Mutation analysis for a Chinese family affected with Escobar syndrome by whole exome sequencing / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To carry out mutation analysis for a Chinese family affected with Escobar syndrome.</p><p><b>METHODS</b>Whole exome sequencing (WES) was employed to detect potential mutation in the proband. Suspected mutations were validated by combining clinical data and result of Sanger sequencing.</p><p><b>RESULTS</b>A homozygous missense mutation c.715C>T (p.R239C) was detected in the proband and his brother who was also affected. The parents and the daughters of the proband carried the heterozygous mutation c.715C>T, while other family members did not carry the mutation.</p><p><b>CONCLUSION</b>Escobar syndrome is a rare genetic disorder. WES is able to discover genetic mutation underlying this disorder and facilitate genetic counseling and prenatal diagnosis for the affected family.</p>

Mutational analysis and prenatal diagnosis in a family affected with hypophosphatemic rickets / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the clinical characteristics and genetic mutation in a family affected with hypophosphatemic rickets.</p><p><b>METHODS</b>Whole exome sequencing (WES) was used to screen potential mutations in genomic DNA extracted from peripheral venous blood sample from the proband. Suspected mutation was confirmed with Sanger sequencing. Amniotic fluid was sampled from the proband for prenatal diagnosis. Potential maternal contamination was excluded by analysis of short tandem repeat (STR) markers.</p><p><b>RESULTS</b>WES has identified a heterozygous c.2058_2059insAGTT (p.L686fs) mutation of the PHEX gene in the proband, which was confirmed by Sanger sequencing in other affected individuals from the family. The mutation was detected in the amniotic fluid sample from the fetus but not among healthy members from the family.</p><p><b>CONCLUSION</b>Identification of the PHEX mutation by WES has facilitated genetic counseling and prenatal diagnosis for the family affected with hypophosphatemic rickets.</p>