The first Chinese intellectual developmental disorder, autosomal recessive 57 patient with two novel MBOAT7 variants.

BACKGROUND: Intellectual disability (ID) is a con neurodevelopmental disorder in children. The genetic etiology of ID is complex, but more subtypes are defined due to the broad application of next-generation sequencing. METHODS: Whole-exome sequencing (WES) and Sanger sequencing was applied in a family with ID. RESULTS: We report a Chinese 7.5-year-old boy, born to non-consanguineous parents. He showed severe intellectual disability, seizures and autistic features. Two previously unreported variants in MBOAT7, c.669C>G (p.(Tyr223*)) and c.1095C>G (p.(Ser365Arg)) were identified by trio-WES. His mother is a heterozygous carrier of the c.1095C>G variant. The c.669C>G variant is a de novo variant which was undetected in his parents. By construction of the full-length cDNA of the patient's MBOAT7, we verified that these two variants were trans-compound heterozygous variants, which support the genetic etiology of this patient. CONCLUSION: This patient is the first Chinese case of intellectual developmental disorder (IDD), autosomal recessive 57 (OMIM:617188) with two unreported MBOAT7 variants.

Case report: A novel compound heterozygous variant in the TNXB gene causes single kidney agenesis and vesicoureteral reflux.

Primary vesicoureteral reflux (VUR) is the prevailing congenital anomaly of the kidneys and urinary tract, posing a significant risk for pyelonephritis scarring and chronic renal insufficiency in pediatric patients. Nevertheless, the precise genetic etiology of VUR remains enigmatic. In this current investigation, we conducted whole-exome sequencing on a child exhibiting single kidney, devoid of any familial VUR background, along with both biological parents. Two missense variants (NM_019105.8: exon11: c.4111G>A and NM_019105.8: exon2: c.31A>T) in the TNXB gene were identified through whole-exome sequencing of the child. These variants were found to be inherited from the child's parents, with each parent carrying one of the variants. Molecular dynamics simulations were conducted to assess the impact of these variants on the tenascin XB proteins encoded by them, revealing varying degrees of impairment. Based on our findings, it is suggested that the TNXB compound heterozygous variant, consisting of c.4111G>A and c.31A>T, may be the underlying cause of right renal agenesis and left hydronephrosis in afflicted child. This discovery broadens the genetic range of the TNXB gene and establishes a genetic foundation for disease-specific preimplantation genetic diagnosis (PGD) in prospective pregnancies involving the parents of this afflicted child.

Compound heterozygous mutations in tripeptidyl peptidase 1 cause rare autosomal recessive spinocerebellar ataxia type 7: A case report.

BACKGROUND: Spinocerebellar ataxia recessive type 7 (SCAR7) is a rare clinical manifestation beginning in childhood or adolescence. SCAR7 is caused by tripeptidyl peptidase 1 (TPP1) gene mutations, and presents with cerebellar ataxia, pyramidal signs, neurocognitive impairment, deep paresthesia, and cerebellar atrophy. CASE SUMMARY: Here, we describe a 25-year-old female patient in China who presented with increasing difficulty walking, falling easily, shaking limbs, instability holding items, slurred speech, coughing when drinking, palpitations, and frequent hunger and overeating. Magnetic resonance imaging showed cerebellar atrophy. Whole exome sequencing detected two compound heterozygous mutations in the TPP1 gene: c.1468G>A p.Glu490Lys and c.1417G>A p.Gly473Arg. Considering the patient's clinical presentation and genetic test results, we hypothesized that complex heterozygous mutations cause TPP1 enzyme deficiency, which may lead to SCAR7. CONCLUSION: We report the first case of SCAR7 from China. We also identify novel compound heterozygous mutations in the TPP1 gene associated with SCAR7, expanding the range of known disease-causing mutations for SCAR7.

Compound heterozygous variants in CFTR with potentially reducing ATP-binding ability identified in Chinese infertile brothers with isolated congenital bilateral absence of vas deferens.

BACKGROUND: Isolated congenital bilateral absence of vas deferens (iCBAVD) in men results in obstructive azoospermia and is mainly caused by pathogenic variants in cystic fibrosis transmembrane conductance regulator (CFTR) or adhesion G protein-coupled receptor G2 (ADGRG2). METHODS: The next-generation sequencing (NGS) was used to screen the mutations in the proband, and Sanger sequencings were performed to validate the compound heterozygous variant of CFTR in his family members. Protein structure simulation was performed to discover the potential pathological mechanism. RESULTS: This study reported novel compound heterozygous CFTR mutations (NM:000492.4, Intron: 5T; c.3965_3969dupTTGGG: p.R1325Gfs*5) in two brothers with obstructive azoospermia. The compound heterozygous CFTR mutations were first screened out by NGS in an infertile male patient who exhibited iCBAVD from a nonconsanguineous Chinese family. Histological analysis of the testicular biopsy from this patient revealed normal spermatogenesis and mature spermatozoa were observed in the seminiferous tubules. Surprisingly, the same compound heterozygous CFTR mutations were also observed in his brothers who also exhibited iCBAVD, with their parents being a heterozygous carrier for the mutations, as verified by Sanger sequencing. Protein structure simulation revealed that these mutations potentially led to impaired ATP-binding ability of CFTR. CONCLUSION: We identified novel compound heterozygous CFTR mutations in two brothers and summarized the literature regarding CFTR mutation and male infertility. Our study may contribute to the genetic diagnosis of iCBAVD and future genetic counseling.

Compound Heterozygous Variants of the CPAMD8 Gene Co-Segregating in Two Chinese Pedigrees With Pigment Dispersion Syndrome/Pigmentary Glaucoma.

The molecular mechanisms underlying the pathogenesis of pigment dispersion syndrome and pigmentary glaucoma remain unclear. In pedigree-based studies, familial aggregation and recurrences in relatives suggest a strong genetic basis for pigmentary glaucoma. In this study, we aimed to identify the genetic background of two Chinese pedigrees with pigmentary glaucoma. All members of these two pedigrees who enrolled in the study underwent a comprehensive ophthalmologic examination, and genomic DNA was extracted from peripheral venous blood samples. Whole-exome sequencing and candidate gene verifications were performed to identify the disease-causing variants; in addition, screening of the CPAMD8 gene was performed on 38 patients of sporadic pigmentary glaucoma. Changes in the structure and function of abnormal proteins caused by gene variants were analyzed with a bioinformatics assessment. Pigmentary glaucoma was identified in a total of five patients from the two pedigrees, as were compound heterozygous variants of the CPAMD8 gene. No signs of pigmentary glaucoma were found in carriers of monoallelic CPAMD8 variant/variants. All four variants were inherited in an autosomal recessive mode. In addition to the 38 patients of sporadic pigmentary glaucoma, 13 variants of the CPAMD8 gene were identified in 11 patients. This study reported a possible association between CPAMD8 variants and pigment dispersion syndrome/pigmentary glaucoma.

CLN8 Gene Compound Heterozygous Variants: A New Case and Protein Bioinformatics Analyses.

The CLN8 disease type refers to one of the neuronal ceroid lipofuscinoses (NCLs) which are the most common group of neurodegenerative diseases in childhood. The clinical phenotypes of this disease are progressive neurological deterioration that could lead to seizures, dementia, ataxia, visual failure, and various forms of abnormal movement. In the current study, we describe two patients who presented with atypical phenotypic manifestation and protracted clinical course of CLN8 carrying a novel compound heterozygous variant at the CLN8 gene. Our patients developed a mild phenotype of CLN8 disease: as they presented mild epilepsy, cognitive decline, mild learning disability, attention-deficit/hyperactivity disorder (ADHD), they developed a markedly protracted course of motor decline. Bioinformatic analyses of the compound heterozygous CLN8 gene variants were carried out. Most of the variants seem likely to act by compromising the structural integrity of regions within the protein. This in turn is expected to reduce the overall stability of the protein and render the protein less active to various degrees. The cases in our study confirmed and expanded the effect of compound heterozygous variants in CLN8 disease.

Case Report: Glycogen Storage Disease Type Ia in a Chinese Child Treated With Growth Hormone.

Background: Glycogen storage disease type Ia is a rare metabolic disorder that leads to excessive glycogen and fat accumulation in organs, characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, puberty delay, and growth retardation. Here, we report on a patient with glycogen storage disease type Ia treated with growth hormone. Case Presentation: A 10-year-old boy had growth retardation for 6 years, and was admitted to clarify the cause of his short stature. We found that his bone age was 5.5 years, significantly lower than his physical age, while his serum IGF-1 and IGFBP-3 were 23.30 and 1620.0 ng/mL, respectively, both lower than normal. His medical history revealed that he had suffered from steatohepatitis, hyperlipidemia, and hypoglycemia since he was 11 months of age. Whole exome sequencing (WES) showed compound heterozygous mutations in exons 2 and 5 of the glucose-6-phosphatase (G6PC) gene on chromosome 17: c.G248A (p.R83H) and c.G648T (p.L216L). The patient was finally diagnosed with GSD Ia. After growth hormone (GH) treatment and corn starch therapy for 14 months, his height significantly increased (by 13 cm). The serum IGF-1 level increased to the normal range but his lipid levels and liver function did not significantly increase. Conclusion: We describe a young patient with a compound heterozygous G6PC variant in a Chinese family; his height increased significantly after growth hormone and corn starch interventions. This case emphasizes that WES is essential for early diagnosis, and that growth hormone treatment may increase the height of patients with GSD Ia safely.

Identification and characterization of novel compound heterozygous variants in FSHR causing primary ovarian insufficiency with resistant ovary syndrome.

Primary ovarian insufficiency (POI) is among the foremost causes of women infertility due to premature partial or total loss of ovarian function. Resistant ovary syndrome (ROS) is a subtype of POI manifested as normal ovarian reserve but insensitive to gonadotropin stimulation. Inactivating variants of follicle-stimulating hormone receptor (FSHR), a class A G-protein coupled receptor, have been associated with POI and are inherited via an autosomal recessive pattern. In this study, we investigated the genetic causes of a primary infertility patient manifested as POI with ROS, and elucidated the structural and functional impact of variants of uncertain significance. Next-generation sequencing (NGS) combined with Sanger sequencing revealed novel compound heterozygous FSHR variants: c.1384G>C/p.Ala462Pro and c.1862C>T/p.Ala621Val, inherited from her father and mother, respectively. The two altered amino acid sequences, localized in the third and seventh transmembrane helix of FSHR, were predicted as deleterious by in silico prediction. In vitro experiments revealed that the p.Ala462Pro variant resulted in barely detectable levels of intracellular signaling both in cAMP-dependent CRE-reporter activity and ERK activation and displayed a severely reduced plasma membrane receptor expression. In contrast, the p.Ala621Val variant resulted in partial loss of receptor activation without disruption of cell surface expression. In conclusion, two unreported inactivating FSHR variants potentially responsible for POI with ROS were first identified. This study expands the current phenotypic and genotypic spectrum of POI.

Novel GLDC Compound Heterozygous Variant Leading to Nonketotic Hyperglycinemia: Case Report and Literature Review.

Nonketotic hyperglycinemia (NKH) is a lethal autosomal recessive disease resulting from alterations in glycine metabolism, commonly caused by mutations in glycine decarboxylase (GLDC). The symptoms of NKH usually manifest in the neonatal period, and can be categorized into severe NKH and attenuated NKH based on the clinical outcome. To date, only a few NKH cases have been reported in China. We here report a case of a neonate with severe NKH carrying a novel compound heterozygous variant in GLDC. The patient was a 68-h-old girl who had progressive lethargy, no crying, and poor sucking ability from birth, and was therefore transferred to our department. On admission, the patient was supported by intubation and ventilation and presented with profound coma. Metabolic investigation indicated a markedly increased glycine concentration both in the plasma and cerebrospinal fluid (CSF). Symptomatic treatments were administered, but the patient's condition did not improve substantially. Whole-exome sequencing identified compound heterozygous mutations (c.1261G>C, p.G421R and c.450 C>G, p.N150K) in GLDC, which were inherited from the mother and the father, respectively. The patient was hospitalized for 8 days in our department and died 2 days after discharge. We further summarize the clinical features, genetic characteristics, administered treatment, and prognosis of previously reported Chinese NKH patients for context. Our results highlight that due to the non-specific clinical phenotypes of NKH and difficulty in obtaining CSF samples, genetic testing is a crucial tool, not only for a diagnosis but also for predicting the clinical outcome and can potentially help to determine the optimal therapeutic strategy.

Child-Onset Cerebellar Ataxia Caused by Two Compound Heterozygous Variants in ADPRS Gene: A Case Report.

Background: Gene variants of ADP-ribosylserine hydrosylase, also known as ADP-ribosylhydrolase-like 2 (ADPRS or ADPRLH2; OMIM: 610624), can cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS, OMIM: 618170), an ultra-rare neurodegenerative autosomal recessive disorder. ADPRS encodes ADP-ribosylhydrolase 3, which removes poly(ADP-ribose) polymers, whose posttranslational addition occurs under stressful conditions. Case Presentation: After a respiratory tract infection, a 30-month-old male patient presented with unsteady gait that rendered walking impossible without external help. Neurological examination revealed acute cerebellar ataxia, electroencephalogram results were abnormal, and brain magnetic resonance imaging revealed slightly widened cerebellar sulci. Laboratory tests showed decreased levels of thyroid-stimulating hormone, and increased levels of plasma lactic acid and serum cardiac enzymes. The cerebrospinal fluid glucose test was positive. Four months after onset, the patient died of sudden convulsions. Using whole exome sequencing, we identified two novel compound heterozygous ADPRS variants: NM_017825.3:c.580C>T (p.Gln194Ter) and NM_017825.3:c.803-1G>A. RNA sequencing indicated that the former mutation might cause nonsense-mediated mRNA decay. The c.803-1G>A variant was found to be a splice-site mutation that leads to the transcriptional retention of intron 5. According to the guidelines of the American College of Medical Genetics and Genomics, the two variants were classified as pathogenic. Conclusion: We present the first report of the existence of two compound heterozygous variants of ADPRS, which leads to CONDSIAS.

Analysis of ARSA gene variant in an infant with late infantile metachromatic leukodystrophy / 中华医学遗传学杂志

Objective@#To detect pathogenic variant of ARSA gene in an infant with late infantile metachromatic leukodystrophy (MLD).@*Methods@#The male proband had an onset of walking dysfunction and seizure at 28 months. Arylsulfatase A activity of his peripheral blood leucocytes was 26.9 nmol/mg.17h, and cranial MRI showed wild symmetrical demyelination. With genomic DNA extracted from his peripheral blood sample, all coding exons and splicing sites of the ARSA gene were subjected to Sanger sequencing. PubMed Protein BLAST system was employed to analyze cross-species conservation of the mutant amino acid. Ucsf chimera software was used to analyze the impact of candidate variants on the secondary structure of the protein product. Impact of potential variants was also analyzed with software including PolyPhen-2, Mutation Taster, SIFT and PROVEAN. Whole-exome sequencing was carried out to identify additional variants which may explain the patient’s condition.@*Results@#The proband was found to harbor compound heterozygous variants of the ARSA gene [c.467G>A (p.Gly156Asp) and c. 960G>A (p.Trp320*)], neither of which was reported previously. As predicted by Ucsf chimera software, the c. 960G>A (p.Trp320*) variant may demolish important secondary structures including α-helix, β-strand and coil of the ARSA protein, causing serious damage to its structure and loss of function. The c. 467G>A (p.Gly156Asp) variant was predicted to be "probably damaging" by PolyPhen-2, Mutation Taster and SIFT software.@*Conclusion@#The patient’s condition may be attributed to the compound heterozygous c. 467G>A (p.Gly156Asp) and c. 960G>A (p.Trp320*) variants of the ARSA gene. Above results have facilitated genetic counseling and prenatal diagnosis for this family.

Combined Immunodeficiency With Late-Onset Progressive Hypogammaglobulinemia and Normal B Cell Count in a Patient With RAG2 Deficiency.

Proteins expressed by recombination activating genes 1 and 2 (RAG1/2) are essential in the process of V(D)J recombination that leads to generation of the T and B cell repertoires. Clinical and immunological phenotypes of patients with RAG deficiencies correlate well to the degree of impaired RAG activity and this has been expanding to variants of combined immunodeficiency (CID) or even milder antibody deficiency syndromes. Pathogenic variants that severely impair recombinase activity of RAG1/2 determine a severe combined immunodeficiency (SCID) phenotype, whereas hypomorphic variants result in leaky (partial) SCID and other immunodeficiencies. We report a patient with novel pathogenic compound heterozygous RAG2 variants that result in a CID phenotype with two distinctive characteristics: late-onset progressive hypogammaglobulinemia and highly elevated B cell count. In addition, the patient had early onset of infections, T cell lymphopenia and expansion of lymphocytes after exposure to herpes family viruses. This case highlights the importance of considering pathogenic RAG variants among patients with preserved B cell count and CID phenotype.

Diagnosis of a case with mental retardation due to novel compound heterozygous variants of TRAPPC9 gene / 中华医学遗传学杂志

Objective@#To explore the genetic basis for a boy with mental retardation.@*Methods@#Clinical data and peripheral blood samples of the family were collected. Potential variants were screened by using a panel for genes associated with intellectual impairment. Suspected variants were verified by PCR and Sanger sequencing.@*Results@#The child presented with mental retardation, language delay and poor self-care. Imaging analysis showed widening of brain fissures and subarachnoid space, and dysplasia of corpus callosum. Three novel heterozygous variants, namely c. 1705T>C(p.S569P), c. 1708dupC (p.R570Pfs*80) and c. 2273delA (p.N758Tfs*22), were identified in the TRAPPC9 gene. The mother of the proband has carried the c. 1708dupC (p.R570Pfs*80) and c. 1705T>C(p.S569P) variants, while his father has carried the c. 2273delA (p.N758Tfs*22) variant.@*Conclusion@#The compound heterozygous variants of the TRAPPC9 gene probably underlie the disease in this family. Considering the clinical and genetic heterogeneity of mental retardation, genetic testing is essential for attaining diagnosis for patients with the relevant phenotype.

Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency.

Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade. Here, we further expand the list of inborn errors of metabolism associated with cutis laxa by describing the clinical presentation of a 17-month-old girl with Leigh-like syndrome due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency, a mitochondrial matrix enzyme that catalyzes the second step of the beta-oxidation spiral of fatty acids and plays an important role in amino acid catabolism, particularly valine.