A case of mental retardation caused by a frameshift variant of SYNGAP1 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with mental retardation.@*METHODS@#Whole exome sequencing was carried out for the child. Candidate variant was screened based on his clinical features and verified by Sanger sequencing.@*RESULTS@#The child was found to harbor a c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant in the SYNGAP1 gene. Bioinformatic analysis suggested it to be pathogenic. The same variant was not detected in either parent.@*CONCLUSION@#The c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant of the SYNGAP1 gene probably underlay the mental retardation in this child. Above finding has expanded the spectrum of SYNGAP1 gene variants and provided a basis for the diagnosis and treatment for this child.

Gene variation analysis and prenatal diagnosis for 54 families with oculocutaneous albinism / 中华围产医学杂志

Objective:To investigate the pathogenic gene locus and prenatal genetic diagnosis of 54 families with oculocutaneous albinism (OCA).Methods:This retrospective study enrolled 54 OCA probands and their families from Gansu Province Maternal and Child Health Care Hospital from May 2014 to May 2020. TYR gene variation screening was performed on the probands by Sanger sequencing. Those with negative results were analyzed by high-throughput sequencing, and further verification was performed on their parents by Sanger sequencing. Among the 54 families, 15 ml amniotic fluid were collected from 16 women at 18-21 gestational weeks in their subsequent pregnancy. Sanger sequencing combined with short tandem repeats sequence for linkage analysis were performed for genetic analysis. All data were analyzed using descriptive statistical analysis. Results:Out of the 54 OCA probands, 48 were diagnosed as OCA1, five were OCA2 and one was OCA4 based on the Sanger sequencing and high-throughput sequencing detection. A total of 26 different variation sites were involved in the 48 OCA1 probands, including 15 missense mutations, five nonsense mutations, three splicing mutations, and three frame-shift mutations, among which, c.929insC (29%, 28/96) was the most frequent mutation, followed by c.896G>A (11%, 11/96), c.832C>T (8%, 8/96) and c.703T>C (5%, 5/96). The diagnosis was confirmed in all 16 fetuses in the 16 families that underwent prenatal diagnosis. Five of them were affected and their mothers chose to terminate the pregnancies, the other 11 pregnancies continued to delivery, including seven heterozygous carriers and four fetuses without the same pathogenic allele as the proband. Maternal contamination was excluded in all prenatal samples using short tandem repeat for linkage analysis. All 11 children were in good health during telephone follow-up one month after birth. Postnatal validations were consistent with the prenatal tests.Conclusions:Genetic diagnosis could accurately identify various types of OCA and help to provide prenatal diagnosis and fertility consultation for subsequent pregnancies.

Wiedemann-Steiner syndrome due to novel nonsense variant of KMT2A gene in a case / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with unexplained global developmental delay (GDD), seizure, and facial deformity.@*METHODS@#Whole exome sequencing (WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of the patient and his parents.@*RESULTS@#WES revealed that the patient has carried a previously unreported de novo heterozygous nonsense c.4906C>T (p.Arg1636Ter) variant of the KMT2A gene, Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.4906C>T variant of KMT2A gene was predicted to be pathogenic (PVS1+ PS2+ PM2+PP3).@*CONCLUSION@#The heterozygous nonsense c.4906C>T (p.Arg1636Ter) variant of the KMT2A gene probably underlay the disease in the child. Above finding has enriched the spectrum of pathogenic variants of the KMT2A gene.

Study on newborn screening for Duchenne muscular dystrophy and diagnostic strategy / 中华医学遗传学杂志

OBJECTIVE@#To establish a newborn screening system for Duchenne muscular dystrophy (DMD) through assessment of MM isoenzyme of creatine kinase (CK-MM) activity.@*METHODS@#The CK-MM level was detected using dry blood spot filter paper from 10 252 male newborns. The results were grouped based on their gestational age, sampling time and intervals between the experiments. The threshold value for CK-MM necessitating genetic testing was determined. Next-generation sequencing (NGS) was carried out for those with a CK-MM value over the threshold, and the result was verified by multiplex ligation-dependent probe amplification (MLPA).@*RESULTS@#Based on the result of non-parametric rank sum test, the median CK-MM concentration has increased with the gestational age, and was inversely correlated with the age of the newborns among unaffected specimens. CK-MM on dry blood spot filter paper can be stable for 14 days at 2-8℃. Statistical analysis of CK-MM value of the 10 252 neonates suggested that the threshold may be set as 700 ng/mL. Exonic deletions were found in 2 confirmed cases, whose CK-MM level was greater than 2000 ng/mL.@*CONCLUSION@#Detection of CK-MM in dry blood spot filter paper has provided an effective method for newborn screening of DMD. This simple and inexpensive method can be used for large-scale screening, which is of great value to the early intervention and treatment of the disease.