Activity

To analyze the clinical features, biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia.

Clinical features, blood spot amino acid profiles and urinary organic acid profiles of the patient were analyzed. Targeted capture, next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene.

The patient presented with poor weight gain, poor feeding, lethargy, and a “sweaty feet” odor 10 days after birth. Biochemical test suggested hyperammonemia. Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine (C5 3. 044, reference range 0.04 – 0.4 μmol/L). Organic acid analysis of her urine sample revealed a high level of isovaleric glycine (669. 53, reference range 0 – 0.5). The child was ultimately diagnosed with isovaleric acidemia, and was found to harbor a paternally derived heterozygous variant c.149G>A (p.R50H) and a maternally derived heterozygous variant c.1123G>A (p.G375S) of the IVD gene. Her elder brother was a heterozygous carrier of c.1123G>A (p.G375S) variant. The c.149G>A (p.R50H) was a known pathogenic variant, while the c.1123G>A (p.G375S) variant was previously unreported.

The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.

The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.

To explore the genetic etiology for a newborn with corneal opacity.

The neonate and her parents were subjected to routine G-banding chromosomal karyotyping analysis. Copy number variation (CNV) was analyzed with low-coverage whole-genome sequencing (WGS) and single nucleotide polymorphism microarray (SNP array).

No karyotypic abnormality was found in the newborn and her parents. Low-coverage WGS has identified a de novo 5.5 Mb microdeletion at chromosome 8q21.11-q21.13 in the neonate, which encompassed the ZFHX4 and PEX2 genes. The result was confirmed by SNP array-based CNV analysis.

The newborn was diagnosed with chromosome 8q21.11 deletion syndrome. ZFHX4 may be one of the key genes underlying this syndrome.

The newborn was diagnosed with chromosome 8q21.11 deletion syndrome. ZFHX4 may be one of the key genes underlying this syndrome.

To investigate the clinical characteristics and genetic variant in a Chinese pedigree affected with thiamine pyrophosphokinase deficiency (TPKD).

Clinical data of the pedigree were analyzed retrospectively and summarized from the perspectives of clinical manifestation, magnetic resonance imaging (MRI), and genotype. Relevant literature was also reviewed.

The proband, a female, has developed paroxysmal ataxia with dystonia at the age of 2-year-and-8-month. The ataxia has recurred for 7-8 times. The child had died at 11 years old due to recurrence and aggravation of the disease. MRI showed diffuse symmetrical lesions of brain parenchyma and spinal cord. Her brother had similar symptoms and died at 6. The parents were consanguineous but healthy. Genetic testing revealed that the girl has carried homozygous c.161C>T variants of the TPK1 gene, suggesting the diagnosis of TPKD. So far 15 cases of TPKD have been reported, among which 9 were from consanguineous marriages. The disease usually occurs before the age of 3, and most patients had featured paroxysmal encephalopathy and recurrent infections. Symmetrical celebral cortex, basal ganglia and cerebellum lesions were common. Missense mutations of the TPK1 gene were common. Vitamin B1 was effective in some cases.

For infants featuring encephalopathy, ataxia, dystonia and other phenotypes, early genetic testing should be recommended in order to provide guidance for clinical treatment and genetic counseling.

For infants featuring encephalopathy, ataxia, dystonia and other phenotypes, early genetic testing should be recommended in order to provide guidance for clinical treatment and genetic counseling.

To explore the genetic basis for a child with unexplained global developmental delay (GDD), seizure, and facial deformity.

Whole exome sequencing (WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of the patient and his parents.

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).

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.

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.

To perform prenatal diagnosis for a woman carrying a balanced translocation.

Clinical phenotype of the woman and her first child was analyzed. Peripheral blood sample of the woman and amniotic fluid sample from two subsequent pregnancies were subjected to chromosomal karyotyping and copy number variation analysis through next-generation sequencing (NGS).

The karyotypes of the woman and her first child were determined as 46,XX,t(5;6)(p15p23) and 46,XX,?der(5),t(5;6)(p15.32;p22.3), respectively. The karyotype of the amniocyte from her second pregnancy was 46,XN,t(5;6)(p15p23). No pathogenic copy number variation was detected. The karyotype of her third pregnancy was 46,XN,?der(5),t(5;6)(p15.32;p22. 3), in addition with a 6.04 Mb deletion at 5p15.33p15.32 (20 000 – 6 060 000) and a 18.50 Mb duplication at 6p25.3p22.3 (160 000 – 18 660 000).

Combined karyotyping analysis and NGS has enabled detection of fetal copy number variations for a woman carrying a balanced chromosomal translocation.

Combined karyotyping analysis and NGS has enabled detection of fetal copy number variations for a woman carrying a balanced chromosomal translocation.

To explore the genetic basis for a patient with intellectual disability.

Whole exome sequencing and Sanger sequencing were carried out for the patient. The result was verified in her family.

DNA sequencing revealed that the patient has carried a heterozygous nonsense c.40C>T (p.Arg14X) variant of the TRIP12 gene, which was de novo in origin. The variant was unrecorded in the Human Gene Mutation Database. Based on the American College of Medical Genetics and Genomics standards and guidelines, the variant was predicted to be pathogenic (PVS1+ PS2+ PP3).

The patient was diagnosed with autosomal dominant intellectual disability due to heterozygous c.40C>T variant of the TRIP12 gene.

T variant of the TRIP12 gene.

To analyze the clinical phenotype and genetic characterization of a child with early infantile epileptic encephalopathy.

The proband was subjected to history taking and was diagnosed based on his clinical manifestation, magnetic resonance imaging (MRI) and whole exome sequencing (WES). check details Sanger sequencing was carried out to determine the origin of pathogenic variant.

The proband unconsciously tilts his head to one side with squint, which revealed an abnormal discharge. MRI indicated suspicious abnormal signal shadow in the left posterior frontal cortex in addition with inflammation signs in the right maxillary sinus and ethmoid sinus. WES revealed that the proband has carried a heterozygous c.5789G>A variant in the CACNAIA gene. The result of Sanger sequencing was in keeping with that of WES. Neither of his parents has carried the same variant.

The heterozygous c.5789G>A variant of the CACNAIA gene probably underlay the early infantile epileptic encephalopathy 42 in the proband, which has a de novo origin.

A variant of the CACNAIA gene probably underlay the early infantile epileptic encephalopathy 42 in the proband, which has a de novo origin.

To explore the genetic basis for a Chinese pedigree affected with amyloidosis cutis dyschromica.

High-throughput sequencing was carried out for the proband. Bioinformatic analysis was used to identify the pathogenic variants. The result was verified by Sanger sequencing.

A homozygous nonsense variant c.565C>T (p.Arg189X) of the GPNMB gene was identified in the proband, his elder brother and younger sister, which resulted a truncated protein with loss of function. The father of the proband was a heterozygous carrier for the variant. The genotype of his mother was unknown since she had passed away. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.565C>T variant was predicted to be likely pathogenic (PS3+ PM2+ PP1+PP3).

The novel homozygous GPNMB variant probably underlay the amyloidosis cutis dyschromica in this pedigree. Above finding has expanded the spectrum of GPNMB gene variants.

The novel homozygous GPNMB variant probably underlay the amyloidosis cutis dyschromica in this pedigree. Above finding has expanded the spectrum of GPNMB gene variants.

To compare the mRNA level of cell proliferation-related genes Twist1, SIRT1, FGF2 and TGF-β3 in placenta mesenchymal stem cells (PA-MSCs), umbilical cord mensenchymals (UC-MSCs) and dental pulp mesenchymal stem cells (DP-MSCs).

The morphology of various passages of PA-MSCs, UC-MSCs and DP-MSCs were observed by microscopy. Proliferation and promoting ability of the three cell lines were detected with the MTT method. Real-time PCR (RT-PCR) was used to determine the mRNA levels of Twist1, SIRT1, FGF2, TGF-β3.

The morphology of UC-MSCs and DP-MSCs was different from that of PA-MSCs. Proliferation ability and promoting ability of the PA-MSCs was superior to that of UC-MSCs and DP-MSCs. In PA-MSCs, expression level of Twist1 and TGF-β3 was the highest and FGF2 was the lowest. SIRT1 was highly expressed in UC-MSCs. With the cell subcultured, different expression levels of Twist1, SIRT1, FGF2, TGF-β3 was observed in PA-MSCs, UC-MSCs and DP-MSCs.

Up-regulated expression of the Twist1, SIRT1 and TGF-β3 genes can promote proliferation of PA-MSCs, UC-MSCs and DP-MSCs, whilst TGF-β3 may inhibit these. The regulatory effect of Twist1, SIRT1, FGF2 and TGF-β3 genes on PA-MSCs, UC-MSCs and DP-MSCs are different.

Up-regulated expression of the Twist1, SIRT1 and TGF-β3 genes can promote proliferation of PA-MSCs, UC-MSCs and DP-MSCs, whilst TGF-β3 may inhibit these. The regulatory effect of Twist1, SIRT1, FGF2 and TGF-β3 genes on PA-MSCs, UC-MSCs and DP-MSCs are different.

To explore the genetic basis for 7 patients with Alström syndrome.

DNA was extracted from peripheral blood samples of the patients and their parents. Whole exome sequencing was carried out for the patients. Suspected variant was verified by Sanger sequencing and bioinformatic analysis.

Genetic testing revealed 12 variants of the ALMS1 gene among the 7 patients, including 7 nonsense and 5 frameshift variants, which included c.5418delC (p.Tyr1807Thrfs*23), c.10549C>T (p.Gln3517*), c.9145dupC (p.Thr3049Asnfs*12), c.10819C>T (p.Arg3607*), c.5701_5704delGAGA (p.Glu1901Argfs*18), c.9154_9155delCT (p.Cys3053Serfs*9), c.9460delG (p.Val3154*), c.9379C>T (p.Gln3127*), c.12115C>T (p.Gln4039*), c.1468dupA (p.Thr490Asnfs*15), c.10825C>T (p.Arg3609*) and c.3902C>A (p.Ser1301*). Among these, c.9154_ 9155delCT, c.9460delG, c.9379C>T, and c.1468dupA were unreported previously. Based on the standards and guidelines of American College of Medical Genetics and Genomics, the c.9379C>T and c.12115C>T variants of the ALMS1 gene were predicted to be likely pathogenic (PVS1+PM2), whilst the other 10 variants were predicted to be pathogenic (PVS1+ PM2+ PP3+PP4).