Phenotype and genotype analyses of Chinese patients with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations

Background: Autosomal dominant mental retardation type 5 (MRD5), a rare neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), developmental delay (DD), and epilepsy predominantly, is caused by a heterozygous mutation in the SYNGAP1 gene. SYNGAP1 mutations have been rarely reported in the Chinese population. Here, we present an investigation of SYNGAP1 mutations in a clinical cohort with ID and DD in Shandong, a northern province in China, to further explore the genotype and phenotype correlations.Methods: A retrospective study was conducted on 10 children with SYNGAP1 mutations presenting ID, DD, and epilepsy who were diagnosed between January 2014 and May 2022. Clinical data and genetic tests were collected. Treatment and regular follow-ups were carried out to pay close attention to the prognosis of the patients.Results: We described 10 unrelated affected individuals with SYNGAP1 mutations, displaying ID, DD, epilepsy, or seizures. All mutations of SYNGAP1 in the 10 patients were de novo, except patient 3 whose father was unavailable, including five nonsense mutations, two frameshift mutations, two splicing mutations, and one codon deletion. Among these mutations, five were novel and the other five were previously reported. Significantly, all patients with epilepsy were sensitive to anti-seizure drugs, especially sodium valproate. Furthermore, rehabilitation training seemed to exert a more improved effect on motor development than language development for the patients.Conclusion The 10 patients carrying SYNGAP1 mutations were diagnosed as MRD5. Five novel genetic mutations were found, which expanded the mutational spectrum of the SYNGAP1 gene. The identification of these mutations in this study helps explore the relationship between genotypes and phenotypes and contributes to genetic counseling and therapeutic intervention for patients with MRD5

Diagnostic application of exome sequencing in Chinese children with suspected inherited kidney diseases

Background: Inherited kidney diseases (IKDs) are a group of kidney diseases characterized by abnormal kidney structure or function caused by genetic factors, but they are not easily diagnosed in childhood due to either nonspecific symptoms and signs or clinically silent symptoms in the early stages until the progressive stages, even end-stages. Early diagnosis of IKDs is very urgent for timely treatment and improving outcomes of patients. So far, the etiological diagnosis has been accelerated with the advance of clinical genetic technology, particularly the advent of next-generation sequencing (NGS) that is not only a powerful tool for prompt and accurate diagnosis of IKDs but also gives therapy guidance to decrease the risk of unnecessary and harmful interventions.Methods: The patients presenting with urinalysis abnormalities or structural abnormalities from 149 Chinese families were enrolled in this study. The clinical features of the patients were collected, and the potentially causative gene variants were detected using exome sequencing. The clinical diagnostic utility of the genetic testing was assessed after more detailed clinical data were analyzed.Result: In total, 55 patients identified having causative variants by exome sequencing were genetically diagnosed, encompassing 16 (29.1%) autosomal dominant IKDs, 16 (29.1%) autosomal recessive IKDs, and 23 (41.8%) X-linked IKDs, with 25 unreported and 45 reported variants. The diagnostic yield was 36.9%. The utility of the exome sequencing was accessed, 12 patients (21.8%) were confirmed to have suspected IKDs, 26 patients (47.3%) discerned the specific sub-types of clinical category, and 17 patients (30.9%) with unknown etiology or lack of typical manifestations were reclassified.Conclusion: Our study supported that genetic testing plays a crucial role in the early diagnosis for children with IKDs, which affected follow-up treatment and prognostic assessment in clinical practice. Moreover, the variant spectrum associated with IKDs was expanded

Generation and characterization of an induced pluripotent stem cell (iPSC) line SDQLCHi063-A from peripheral blood mononuclear cells of a patient with Maturity-onset diabetes of the young type 2 carrying GCK exon 1 deletion

Maturity-onset diabetes of the young type 2 (MODY2) is an autosomal dominant disorder caused by mutations in the GCK gene. It is characterized by a non-progressive slight increase in glycosylated hemoglobin (HbA1c), and mildly raised fasting glucose. Here, we generated an induced pluripotent stem cell line SDQLCHi063-A from a five-year-old boy with MODY2 carrying exon 1 deletion of the GCK gene (OMIM*138079). The iPSC line carries original gene mutation, expresses pluripotency markers, has normal karyotype and differentiated spontaneously in the three germ layers

Establishment of a non-integrated iPSC (SDQLCHi068-A) line derived from a patient with autosomal dominant immunodeficiency-14A carrying a heterozygous mutation (c.3061G>A) in PIK3CD gene

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD) gene (OMIM#602839) encodes the p110δ catalytic subunit, mainly expressed in immune cells, and is associated with autosomal dominant immunodeficiency-14A with lymphoproliferation (IMD14A, #615513). We generated a human iPS cell line from a 50-month-old boy with IMD14A carrying a heterozygous mutation (c.3061G>A, p.E1021K) in PIK3CD gene. This cell line retains the original mutation site and shows differentiation potential towards three germ layers in vitro, which can be used as a disease model for research

Establishment of iPS cell line (SDQLCHi061-A) from a patient with carbamoylphosphate synthetase I deficiency due to CPS1 mutation

The induced pluripotent stem cells (iPSCs) line was generated using peripheral blood mononuclear cells (PBMCs) from a patient with compound heterozygous mutation of c.2374A > G/p.M792V and c.3949C > T/p.R1317W in the CPS1 gene by non-integrating vectors. The expression of pluripotency markers, potential for in vitro trilineage differentiation and exhibiting normal karyotype were demonstrated in the SDQLCHi061-A cell line. This cell line could provide a useful CPS1D model in vitro for further study

Generation of a transgene-free iPS cell line (SDQLCHi053-A) from a young girl carrying a heterozygous mutation (c.427C > T) in SYNGAP1 gene

The pathogenic mutations of Synaptic Ras GTPase-activating protein 1 (SYNGAP1) gene (OMIM #603384) have been tightly associated with a neurodevelopmental disease, also called autosomal dominant mental retardation type 5 (MRD5, OMIM #612621). We generated a human iPS cell line from a 34-month-old young girl bearing a recurrent heterozygous mutation (c.427C > T) of SYNGAP1. This cell line has great performance in pluripotency and shows differentiation potential towards three germ layers in vitro

Establishment of a non-integrated iPSC line (SDQLCHi043-A) from a male infant with propionic acidemia carrying compound heterozygote mutations in PCCB gene

In this study, peripheral blood mononuclear cells were contributed from a male infant with propionic acidemia (PA) verified by clinical and genetic diagnosis, who inherited compound heterozygous mutations in the propionyl-CoA carboxylase subunit beta (PCCB) gene. Here, this iPS was generated by non-integrated episomal vectors with SOX2, BCL-XL, OCT4, C-MYC and OCT4. Also, this iPSC line exhibited the morphology of pluripotent stem cells, upward mRNA and protein expression of pluripotency markers, conspicuous in vitro differentiation potency and regular karyotype, and carried PCCB gene mutations, which provided an excellent model for the research and drug screening of PA