Identification of a novel phenotype of external ear deformity related to Coffin-Siris syndrome-9 and literature review.

De novo germline variants of the SRY-related HMG-box 11 gene (SOX11) have been reported to cause Coffin-Siris syndrome-9 (CSS-9), a rare congenital disorder associated with multiple organ malformations, including ear anomalies. Previous clinical and animal studies have found that intragenic pathogenic variant or haploinsufficiency in the SOX11 gene could cause inner ear malformation, but no studies to date have documented the external ear malformation caused by SOX11 deficiency. Here, we reported a Chinese male with unilateral microtia and bilateral sensorineural deafness who showed CSS-like manifestations, including dysmorphic facial features, impaired neurodevelopment, and fingers/toes malformations. Using trio-based whole-exome sequencing, a de novo missense variant in SOX11 (NM_003108.4: c.347A>G, p.Y116C) was identified and classified as pathogenic variant as per American College of Medical Genetics guidelines. Moreover, a systematic search of the literature yielded 12 publications that provided data of 55 SOX11 intragenic variants affecting various protein-coding regions of SOX11 protein. By quantitatively analyzing phenotypic spectrum information related to these 56 SOX11 variants (including our case), we found variants affecting different regions of SOX11 protein (high-mobility group [HMG] domain and non-HMG regions) appear to influence the phenotypic spectrum of organ malformations in CSS-9; variants altering the HMG domain were more likely to cause the widest range of organ anomalies. In summary, this is the first report of CSS with external ear malformation caused by pathogenic variant in SOX11, indicating that the SOX11 gene may be not only essential for the development of the inner ear but also critical for the morphogenesis of the external ear. In addition, thorough clinical examination is recommended for patients who carry pathogenic SOX11 variants that affect the HMG domain, as these variants may cause the widest range of organ anomalies underlying this condition.

Progressive encephalomyelitis with rigidity and myoclonus: a pediatric case report and literature review.

BACKGROUND: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and life-threatening autoimmune disease of the central nervous system. So far, only ten cases of PERM have been reported in children worldwide, including the one in this study. CASE PRESENTATION: We report a case of an 11-year-old boy with PERM with an initial presentation of abdominal pain, skin itching, dysuria, urinary retention, truncal and limb rigidity, spasms of the trunk and limbs during sleep, deep and peripheral sensory disturbances, and dysphagia. A tissue-based assay using peripheral blood was positive, demonstrated by fluorescent staining of mouse cerebellar sections. He showed gradual and persistent clinical improvement after immunotherapy with intravenous immunoglobulin, steroids, plasmapheresis and rituximab. CONCLUSIONS: We summarized the diagnosis and treatment of a patient with PERM and performed a literature review of pediatric PERM to raise awareness among pediatric neurologists. A better comprehension of this disease is required to improve its early diagnosis, treatment, and prognosis.

Clinical significance of nonerythrocytic spectrin Beta 1 (SPTBN1) in human kidney renal clear cell carcinoma and uveal melanoma: a study based on Pan-Cancer Analysis.

BACKGROUND: Nonerythrocytic spectrin beta 1 (SPTBN1) is an important cytoskeletal protein that involves in normal cell growth and development via regulating TGFß/Smad signaling pathway, and is aberrantly expressed in various cancer types. But, the exact role of SPTBN1 in pan-cancer is still unclear. This report aimed to display expression patterns and prognostic landscapes of SPTBN1 in human cancers, and further assess its prognostic/therapeutic value and immunological role in kidney renal carcinoma (KIRC) and uveal melanoma (UVM). METHODS: We firstly analyzed expression patterns and prognostic landscapes of SPTBN1 in human cancers using various databases and web-based tools. The relationships between SPTBN1 expression and survival/tumor immunity in KIRC and UVM were further investigated via R packages and TIMER 2.0 platform. The therapeutic roles of SPTBN1 in KIRC and UVM were also explored via R software. Following this, the prognostic value and cancer immunological role of SPTBN1 in KIRC and UVM were validated in our cancer patients and GEO database. RESULTS: Overall, cancer tissue had a lower expression level of SPTBN1 frequently in pan-cancer, compared with those in adjacent nontumor one. SPTBN1 expression often showed a different effect on survival in pan-cancer; upregulation of SPTBN1 was protective to the survival of KIRC individuals, which was contrary from what was found in UVM patients. In KIRC, there were significant negative associations between SPTBN1 expression and pro-tumor immune cell infiltration, including Treg cell, Th2 cell, monocyte and M2-macrophage, and expression of immune modulator genes, such as tumor necrosis factor superfamily member 9 (TNFSF9); while, in UVM, these correlations exhibited opposite patterns. The following survival and expression correlation analysis in our cancer cohorts and GEO database confirmed these previous findings. Moreover, we also found that SPTBN1 was potentially involved in the resistance of immunotherapy in KIRC, and the enhance of anti-cancer targeted treatment in UVM. CONCLUSIONS: The current study presented compelling evidence that SPTBN1 might be a novel prognostic and therapy-related biomarker in KIRC and UVM, shedding new light on anti-cancer strategy.

Development and validation of a nomogram based on common biochemical indicators for survival prediction of children with high-risk neuroblastoma: A valuable tool for resource-limited hospitals.

BACKGROUND: Despite multiple attempts have been made to develop risk stratification within high-risk neuroblastoma (NB) patients (age of diagnosis ≥ 18 month-old with metastatic NB), the definition of "ultra high-risk NB" is still lack of consensus, and indicators for identifying this subgroup are still unclear. This study aimed to develop a nomogram based on easy-to-obtain blood-derived biofactors for identifying ultra high-risk NB patients with highest risk of death within 3 or 5 years. METHODS: One hundred sixty-seven NB patients who treated at Sun Yat-sen University Cancer Center between 2015 and 2023 were recruited and clustered randomly into training and validation cohorts (116 and 51 cases, respectively). Univariate and multivariate Cox analysis were performed in training set to screen independent prognostic indicators for constructing nomogram model of predicting 1-, 3- and 5-year overall survival (OS). The discrimination power of the nomogram in training and validation sets were assessed by concordance index (C-index) and calibration plot. Based on the risk score obtained from nomogram model, the prognostic accuracy of 1-, 3- and 5-year OS rates in training and validation cohorts were further evaluated using the area under receiver operating characteristic (ROC) curves (AUC). RESULTS: Through univariate and multivariate Cox analysis, independent prognostic indicators, including serum lactate dehydrogenase (LDH) and albumin (ALB), were identified in training set, and used to establish a nomogram model. The model showed good discrimination power with C-index in training cohort being 0.706 (95%CI: 0.633-0.788). According to the cut-point calculated based on the established nomogram, patients with a nomogram score > 34 points could be stratified to ultra high-risk NB subgroup, and this subgroup had poorer OS than those in non-ultra one (p < 0.001). AUC values of ROC curves for 3- and 5-year OS rates in the training set were 0.758 and 0.756, respectively. Moreover, based on the cut-point score (34 points) developed in training set, The model also showed good discrimination power with C-index of 0.773 (95%CI: 0.664-0.897) and powerful prognostic accuracy of AUC for 3- and 5-year OS rates being 0.825 and 0.826, respectively, in validation cohort. CONCLUSIONS: We developed a simple-to-use nomogram based on common laboratory indicators to identify the subgroup of ultra high-risk NB before treatment, providing these children even from developing countries or regions access to intensified multimodal treatments earlier and thus improving their long-term outcome.

[Identification of a novel frameshift variant in the KMT2A gene of a child with Wiedemann-Steiner syndrome].

OBJECTIVE: To analyze pathogenic variant s of KMT2A gene in a child with Wiedemann-Steiner syndrome (WDSTS) and provide reliable evidences for clinical diagnosis of WDSTS. METHODS: Whole-DNAs were extracted from an 9 years-old boy and his parents. Trio-whole exome sequencing (trio-WES) was performed to identify candidate pathogenic variants that can explain the boy's condition and sanger sequencing was conducted to prove it. The impact of detected variants were predicted and validated by bioinformatics tools. RESULTS: A de novo frameshift variant c.10488dupG (p.Leu3498Thrfs*41) in exon 27 of KMT2A gene was detected and this de novo variant (PS2) had not been reported in the world previously. This frameshift variant was absent in major allele frequency databases (PM2) and had been predicted to be pathogenic based on MutationTaster. Through HomoloGene and CD-search system, the 3498 locus (Leu) in KMT2A protein, which was an important histone modifying enzyme that regulated gene expression in early embryonic development and encoded by the KMT2A gene, was predicted as a high conserved locus (PP3), and that replacement of Lue3498 may result in frame-shifts with premature termination in 3539 locus by introducing stop codon, causing deletion of multiple functional domains which all played important roles on histone modifications and recognition (PVS1+PM1). According to the American College of Medical Genetics and Genomics variant classification guideline, the variant c.10488dupG (p.Leu3498Thrfs*41) in KMT2A was classified as pathogenic variant (PVS1+PS2+PM1+PM2+PP3). CONCLUSION: The patient's condition may be attributed to the de novo frameshift variant c.10488dupG (p.Leu3498Thrfs*41) in KMT2A gene. This study reported a pathogenic KMT2A variant that had not been reported previously in WDSTS, it expanded the genotypic spectrums of KMT2A variants.

[Analysis of SSR4 gene variant in a child with congenital glycosylation type 1y in conjunct with congenital dysplasia of external auditory canal].

OBJECTIVE: To explore the genetic basis for a child with congenital disorder of glycosylation type 1y (CDG-1y) in conjunct with congenital dysplasia of external auditory canal. METHODS: Trio-whole exome sequencing (trio-WES) was carried out for the family. Candidate variant was verified by Sanger sequencing. Pathogenicity of the variant was predicted with a variety of bioinformatic tools. RESULTS: The proband, a 10-years-old boy, presented with mental retardation, microcephaly and dysplasia of external auditory canal. Trio-WES revealed that he has harbored a de novo frameshift variant c.302dupC (p.Y102Lfs*2) in exon 4 of SSR4 gene, which was unreported previously (PS2). The variant was absent in major allele frequency databases (PM2) and was predicted to be pathogenic by multiple bioinformatic tools (PP3). UCSF chimera software suggested that the c.302dupC (p.Y102Lfs*2) variant can induce significant alteration to the structure of SSR4 protein, resulting loss of function (PVS1+PM1). Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was classified as pathogenic (PVS1+PS2+PM1+PM2+PP3). CONCLUSION: The de novo frameshift variant c.302dupC (p.Y102Lfs*2) of the SSR4 gene probably underlay the child's condition. Above finding has enriched the spectrum of SSR4 mutations and the phenotypic spectrum of CDG-1y.

DNA index as prognostic factor in childhood acute lymphoblastic leukemia in the COG-TARGET database.

BACKGROUND: This study was aimed to evaluate the value of DNA index(DI) among pediatric acute lymphoblastic leukemia (ALL) treated on Children's Oncology Group (COG) protocols between 2000 and 2015. METHODS: Retrospective study were analysis among pediatric ALL patients from the TARGET dataset. RESULT: Totally, 1668 eligible pediatric patients were enrolled in this study. Of them, 993 are male and 675 are female with a median age of 7.6 years old. The median follow-up for those patients was 7.7 years (range 0.1-15.7 years). The probability of 15-year EFS and OS were reported to be 67.5 ± 3.1% and 78.3 ± 2.5%, respectively. BCR/ABL1 fusion gene affected the early treatment response and the survival of childhood ALL. Moreover, those patients with ETV6/RUNX1 fusion gene were also significantly associated with better EFS (HR = 0.6, 95% CI 0.4-0.8, P = 0.003) and OS (HR = 0.3, 95%CI 0.2-0.5, P < 0.001) compared to patients with no ETV6/RUNX1. On the contrary, BM NR on Day+ 29 showed a significant decrease in EFS (HR = 3.1, 95%CI 2.1-4.5, P < 0.001) and OS (HR = 1.7, 95%CI 1.1-2.8, P = 0.026). Multivariate analysis showed that DI was significantly associated with better EFS and OS. The threshold effect of DI on poor outcome was significant after adjusting for potential confounders. The adjusted regression coefficient (Log RR) was 0.7 (95%CI 0.1-3.2, P = 0.597) for DI < 1.1 while 8.8 (95%CI 1.4-56.0, P = 0.021) for DI ≥ 1.2 and 0.0 (95%CI 0.0-0.8, P = 0.041) for 1.1 ≤ DI < 1.2. Generalized additive models revealed that the lowest rates of the adverse outcomes estimated to occur among DI between 1.1 and 1.2. CONCLUSION: For those childhood ALL treated on COG protocols between 2000 and 2015, ETV6/RUNX1 and BM NR were closely related to the prognosis. Moreover, the DI between 1.1 and 1.2 can serve as a significant cut-point discriminating the risk group, which indicated a favourable prognostic factor.

Eltrombopag as first-line treatment for thrombocytopenia among paediatric patients after allogeneic haematopoietic stem cell transplantation.

AIMS: The purpose of this study is to examine the safety and efficacy of eltrombopag as first-line treatment for thrombocytopenia among paediatric patients after haematopoietic stem cell transplantation (HSCT). METHODS: Forty-three childhood patients with thrombocytopenia after HSCT who received eltrombopag were retrospectively analysed. RESULT: Eltrombopag was began at the median of 27 days after HSCT and lasted for 24 days. Thirty-five children responded to eltrombopag therapy, and the cumulative platelet recovery rate was 88.9%. The cumulative incidence of platelet recovery was lower (83.9 vs 100%; P = .035) in patients with decreased numbers of megakaryocytes before starting eltrombopag than in those with normal. Factors associated with a significantly elevated response to eltrobopag from univariate analysis were donor type. Results from the multiple regression analysis found that weight (hazard ratio [HR] = 0.7, 95% confidence interval [CI] 0.5-0.9, P = .022), platelet engraftment time (HR = 1.0, 95%CI 1.0-1.0, P = .012) and bone marrow megakaryocytes (HR = 8.0, 95%CI 1.5-43.3, P = .016) before starting eltrombopag were the independent risk factors. Based on Youden's index algorithm in the receiver-operating characteristic curve, the optimal cut-off value of the maintenance dose of eltrombopag in predicting nonresponders was 4 mg/kg. The area under the receiver-operating characteristic curve was 0.923 with sensitivity of 97.8%, specificity of 87.9%, positive predictive value of 72.3%, and negative predictive value of 92%. None of the paediatric patients stopped using eltrombopag due to side effect or intolerability. CONCLUSION: Eltrombopag is effective and safe in paediatric patients with thrombocytopenia after HSCT. The number of megakaryocytes in bone marrow before eltrombopag treatment may serve as a predictor of the response to eltrombopag. We recommend that the maintenance dose of eltrombopag should not exceed 4 mg/kg/d.

[Analysis of a child with congenital muscular dystrophy due to a novel variant of the LMNA gene].

OBJECTIVE: To report on a patient with congenital muscular dystrophy (CMD) due to a missense variant of LMNA gene and explore its pathogenicity. METHODS: The 1-year-and-1-month-old boy has presented with motor development delay and elevation of muscle enzymes for more than half a year. Congenital myopathy was suspected. Following muscle biopsy, HE staining, immunostaining and electron microscopy were conducted to clarify the clinical diagnosis. Meanwhile, DNA was extracted from the child and his parents' peripheral venous blood samples. Trio-whole exome sequencing (trio-WES) was carried out to detect pathogenic variant in the child. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: Both light and electron microscopy showed a large area of necrotic muscle tissues with infiltration of inflammatory cells. Immunohistochemistry revealed a large amount of muscle cells to be diffusely positive for Dysferlin. The patient's motor delays, elevations of muscle enzymes and histopathological results suggested a clinical diagnosis of CMD. A de novo missense c.1072G>A (p.E358K) variant was detected in the LMNA gene by trio-WES. The variant was unreported previously (PS2) and was absent from major allele frequency databases (PM2). It was a loss of function variant and was considered as hotspot variant in the LMNA gene (PM1) as the amino acid (E), located in position 358, was highly conserved, and change of this amino acid was found to cause destruction of the filament domain (AA: 30-386), which may result in serious damage to the intermediate filament protein. Furthermore, c.1072G>A (p. E358K) in LMNA gene was also predicted to be pathogenic based on MutationTaster, PROVEAN and PolyPhen-2 (PP3) analysis. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified to be likely pathogenic (PS2+PM1+PM2+PP3). CONCLUSION: The child's condition may be attributed to the de novo missense c.1072 G>A (p.E358K) variant of the LMNA gene. Above discovery has expanded the variant spectrum of the LMNA gene.

[Identification of a novel missense variant of the KAT6B gene in a child with Say-Barber-Biesecker-Young-Simpson syndrome].

OBJECTIVE: To explore the genetic basis for a child suspected for Say-Barber-Biesecker-Young-Simpson syndrome. METHODS: Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing was carried out for the proband. Suspected variants were validated by Sanger sequencing. The impact of the variants was predicted by bioinformatic analysis. RESULTS: The child was found to harbor a de novo missense variant c.2623C>T (p.Asp875Tyr) in exon 13 of the KAT6B gene. The variant was previously unreported, and was not recorded in the major allele frequency database and predicted to be pathogenic based on PolyPhen-2, MutationTaster and PROVEAN analysis. As predicted by UCSF chimera and CASTp software, the variant can severely impact the substrate-binding pocket of histone acetyltransferase, resulting in loss of its enzymatic activity. Based on standards and guidelines by the American College of Medical Genetics and Genomics, the variant was classified to be likely pathogenic (PS2+PM2+PP3). CONCLUSION: The child's condition may be attributed to the de novo missense c.2623C>T (p.Asp875Tyr) variant of the KAT6B gene.

[Clinical and genetic analysis of a family with autosomal dominant-familial Mediterranean fever].

OBJECTIVE: To analyze a pathogenic variant of MEFV gene in a family with autosomal dominant-familial Mediterranean fever (AD-FMF). METHODS: A 5-year-old boy presented with recurrent aseptic meningitis and his major symptoms included recurrent fever with headache and vomiting. His family members including his mother, sister and brother also had recurrent fever. A genetic disease was considered. DNAs were extracted from patient and all his family members' blood samples. Whole exome sequencing was performed to identify putative pathogenic variants that can explain this family's condition and Sanger sequencing was conducted. The impact of detected variants were predicted and validated by bioinformatics. RESULTS: A missense variant c.2229C>G (p.Phe743Leu) in MEFV gene was identified in the proband and his family members including his mother, sister and brother. This variant had not been reported in China previously, but the locus of it had already been reported in Arabic patient with AD-FMF (PS1). This variant was absent in major allele frequency databases (PM2) and had been predicted to be pathogenic based on Mutationtaster, PROVEAN and PolyPhen-2. In addition, the change of amino acid, locating in 743 locus of pyrin protein, encoding by MEFV gene, was found to cause SPRY_PRY_TRIM20 and SPRY_superfamily domain destroyed and finally influenced the fuction of pyrin protein. On the other hand, using UCSF chimera software, we find the variant c.2229C>G (p.Phe743Leu) can induce serious influence to the spatial structure of pyrin protein and loss of protein fuction (PP3). According to the ACMG variant classification guideline, the variant c.2229C>G (p.Phe743Leu) in MEFV gene was classified as likely pathogenic (PS1+PM2+PP3). CONCLUSION: The condition of this AD-FMF family may be attributed to the missense variant c.2229C>G (p.Phe743Leu) in MEFV gene. The recurrent aseptic meningitis was a very rare manifestation in AD-FMF patients and had not been reported in China previously. The clinical and genetic findings of the present study are helpful for the further understanding of AD-FMF.

Rituximab may cause higher mortality in young autoimmune disease patients with rituximab-induced interstitial lung disease: A case report and systematic review of the literature.

BACKGROUND: MOG-IgG-associated encephalomyelitis (MOG-EM), a of common type of autoimmune encephalomyelitis (AE), is an autoimmune disease (AID) of the central nervous system that predominantly affects the brain and spinal cord. Rituximab (RTX) - a chimeric anti-CD20 monoclonal antibody - has been increasingly used as an effective immunotherapeutic agent in the treatment of AE. However, interstitial lung disease (ILD) is an exceedingly rare but potentially fatal complication of RTX treatment. Case report and review of the literature: Herein, we describe the first case of RTX-induced ILD (R-ILD) in a teenager with MOG-EM. In addition, we systematically review the literature on R-ILD cases in patients with AID and discuss the clinical characteristics of R-ILD in individuals with differential diagnosis of AID. CONCLUSION: R-ILD should be suspected in patients with AE undergoing RTX treatment who present with dyspnea and/or cough without any signs or symptoms of infection. Meanwhile, by reviewing the literature systematically, we suggest that regardless of the dosage, RTX therapy for AID should be very cautious and well-monitored especially in young individuals including age groups of children, adolescents, and young adults due to the possibility of relatively higher mortality caused by R-ILD.

[Identification of a novel nonsense IQSEC2 variant in a child with X-linked intellectual disability].

OBJECTIVE: To explore the genetic basis for a child featuring X-linked intellectual disability. METHODS: The 1-year-and-6-month-old child presented with growth retardation, intellectual disability and bilateral alternating squint. With DNA extracted from the child and his parents' peripheral venous blood samples, whole exome sequencing was carried out to identify potential variants that can explain his condition. Suspected variants were validated by Sanger sequencing. The impact of variants was predicted by bioinformatic tools. RESULTS: The child was found to harbor a de novo nonsense c.3163C>T (p.Arg1055*) variant of the IQSEC2 gene. The variant, unreported previously, was predicted to be pathogenic based on MutationTaster, PROVEAN and SIFT. Analysis using a HomoloGene system suggested Arg1055 in IQSEC2 residues to be highly conserved evolutionarily, and that replacement of Arg1055 may cause destroy of the PH domain (AA 951-1085) and serious damage to the function of IQSEC2 protein. Analysis with UCSF chimera software suggested that the c.3163C>T (p.Arg1055*) variant can induce serious damages to the secondary structures of IQSEC2 protein, causing loss of its function. CONCLUSION: The patient's condition may be attributed to the de novo nonsense variant c.3163C>T (p.Arg1055*) of the IQSEC2 gene.

[Identification of a novel frameshift variant in the SRCAP gene of a child with Floating-Harbor syndrome].

OBJECTIVE: To explore the molecular basis for a child featuring with Floating-Harbor syndrome. METHODS: The 2-year-and-8-month-old child presented with retarded growth and language development. Genomic DNA was extracted from peripheral blood samples from the child and his parents with informed consent and subjected to whole exome sequencing. Suspected variants were verified by Sanger sequencing. Pathogenecity of the variants were predicted by using bioinformatic tools. RESULTS: The child was found to carry a de novo frameshift variant c.7273dupA (p. Thr2425Asnfs*18) in the SRCAP gene. The variant was unreported previously and predicted to be pathogenic by MutationTaster. Analysis using HomoloGene system and MEGA software indicated position 2425 of the SRCAP protein to be highly conserved. Substitution of amino acid (Thr) at this position may cause destruction of three AT-hook domains (Amino acid 2857-2869, 2936-2948 and 3004-3016) and serious damage to the function of SRCAP protein. CONCLUSION: The patient's condition may be attributed to the de novo frameshift variant c.7273dupA (p. Thr2425Asnfs*18) of the SRCAP gene. Above finding can facilitate diagnosis of Floating-Harbor syndrome among Chinese population.

[Identification of a novel missense NIPBL variant in a juvenile with severe type of Cornelia de Lange syndrome].

OBJECTIVE: To detect pathogenic variant in a juvenile with severe type Cornelia de Lange syndrome (CdLS). METHODS: A 12-year-old female presented with comprehensive developmental retardation and deformity of lower limbs. Genomic DNA was extracted from peripheral blood sample of the patient. Whole exome sequencing was performed to identify pathogenic variants. Putative variant was verified by Sanger sequencing. The impact of variants was predicted and validated by bioinformatic analysis. RESULTS: A de novo missense variant, c.1507A>G (p. Lys503Glu), was found in the NIPBL gene of the proband. The variant was unreported previously and predicted to be pathogenic by PolyPhen-2, MutationTaster and SIFT. Using HomoloGene system, the 503 loci in the NIPBL protein are highly conserved. The change of amino acid (Glu), locating in 503 locus, was found to cause the Neuromodulin_N superfamily domain destroyed, resulting in severe damage to the function of NIPBL protein. CONCLUSION: The de novo missense variant c.1507A>G (p. Lys503Glu) of the NIPBL gene probably underlies the disease in this patient.

[Identification of a novel de novo variant of CSNK2A1 gene in a boy with Okur-Chung neurodevelopmental syndrome].

OBJECTIVE: To analyze pathogenic variant of CSNK2A1 gene in a boy with Okur-Chung neurodevelopmental syndrome (OCNS). METHODS: The 8-year-old boy presented with growth retardation, intellectual disability and spells of breath holding. With genomic DNA extracted from peripheral blood samples of the patient and his parents, whole exome sequencing was carried out. Putative pathogenic variants were verified with Sanger sequencing. The nature and impact of detected variants were predicted through bioinformatic analysis. RESULTS: A novel de novo missense variant c.149A>G (p.Tyr50Cys) of the CSNK2A1 gene was identified, which was unreported previously. The variant was predicted to be pathogenic by PolyPhen-2, Mutation Taster and SIFT software. Based on a HomoloGene system, 50 loci within the CK2alpha protein are highly conserved. The change of amino acid (Cys) at position 50 has destroyed the ATP binding loop domain, causing serious damage to its function. As predicted by a Swiss PDB viewer, the variant can significantly alter the spatial structure of CK2alpha, resulting in loss of protein function. CONCLUSION: The patient's condition may be attributed to the novel de novo missense variant c.149A>G (p.Tyr50Cys) of the CSNK2A1 gene.

[Analysis of ARSA gene variant in an infant with late infantile metachromatic leukodystrophy].

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, ß-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.

[Analysis of HEXB gene mutations in an infant with Sandhoff disease].

OBJECTIVE: To detect potential mutations of HEXB gene in an infant with Sandhoff disease (SD). METHODS: Genomic DNA was extracted from peripheral blood sample of the infant. All coding exons (exons 1 to 14) and splicing sites of the HEXB gene were subjected to PCR amplification and direct sequencing.PubMed Protein BLAST system was employed to analyze cross-species conservation of the mutant amino acid. PubMed BLAST CD-search was performed to identify functional domains destroyed by thecandidate mutations. Impact of the mutations was analyzed with software including PolyPhen-2, Mutation Taster and SIFT. Whole-exome sequencing was carried out to identify additional mutations. RESULTS: The infant was found to carry compound heterozygous mutations c.1652G>A(p.Cys551Tyr) and c.1389C>G (p.Tyr463*) of the HEXB gene. The c.1389C>G (p.Tyr463*) mutation may lead to destruction of two functional domains in ß subunit of the Hex protein. The c.1652G>A(p.Cys551Tyr) mutation, unreported previously,was predicted to be probably damaging by Bioinformatic analysis. CONCLUSION: Compound heterozygous mutations c.1652G>A(p.Cys551Tyr) and c.1389C>G (p.Tyr463*) in the HEXB gene probably underlie the disease in this patient.

[Analysis of PMM2 gene variant in an infant with congenital disorders of glycosylation type 1a].

OBJECTIVE: To identify potential mutation of PMM2 gene in an infant with congenital disorders of glycosylation type 1a (CDG-1a). METHODS: Genomic DNA was extracted from peripheral blood sample of the patient. All coding exons (exons 1-8) and splicing sites of the PMM2 gene were amplified with PCR. Potential variants were detected by direct sequencing of the PCR products and comparing the results against the ESP and SNP human gene databases. A protein BLAST system was employed to analyze cross-species conservation of the variants amino acid. A PubMed BLAST CD-search system was employed to identify functional domains damaged by variants of the PMM2 gene. Impact of potential variants was analyzed using software including PolyPhen-2 SIFT and Mutation Taster. Whole exome sequencing was used to identify additional variants of the PMM2 gene which may explain the condition of the patient. RESULTS: The child was found to carry compound heterozygous variants (c.458_462delTAAGA and c.395T>C) of the PMM2 gene, which were inherited respectively from his father and mother. The c.458_462delTAAGA has not been reported previously and may result in disruption of 10 functional domains within the PMM2 protein. The c.395T>C mutation has been recorded by a SNP database with frequency unknown. Both mutations were predicted as "probably damaging". Whole exome sequencing has identified no additional disease-causing variant which can explain the patient's condition. CONCLUSION: The patient's condition may be attributed to the compound heterozygous variants c.458_462delTAAGA and c.395T>C of the PMM2 gene. Above results has facilitated molecular diagnosis for the patient.

X-linked Hyper-IgM Syndrome: A Phenotype of Crohn's Disease with Hemophagocytic Lymphohistiocytosis.

X-linked hyper-immunoglobulin M (IgM) syndrome is characterized by recurrent infections, low or undetectable levels of IgG and IgA, and normal to increased serum IgM, and is also rare. It is associated with mutation in the gene encoding CD40 ligand. This study aimed to describe the first international report of hemizygous CD40LG c.542G>A mutation in a 5-year-old boy with a phenotype of Crohn's disease and hemophagocytic lymphohistiocytosis. Also, the clinical implications of this mutation and associated atypical phenotype are discussed.