UNASSIGNED: Genetic and acquired risk factors are fundamental to developing venous thromboembolism. Autosomal dominant protein S deficiency caused by pathogenic mutations in the PROS1 gene is a well-known risk factor for thrombophilia.
UNASSIGNED: We report a 30-year-old male patient who presented to the hospital with portal vein thrombosis. The patient had a history of abdominal pain for one month. Abdominal vascular CT showed venous thrombosis in the portal vein and superior mesenteric vein. He was diagnosed with \"portal and superior mesenteric vein thrombosis, small bowel obstruction and necrosis, acute upper gastrointestinal bleeding (UGIB), hemorrhagic shock.\" Serum protein S levels were decreased, and gene sequencing revealed a heterozygous missense mutation in PROS1, c.1571T > G (p.Leu584Arg). The patient received anticoagulation therapy with Enoxaparin Sodium and rivaroxaban, transjugular intrahepatic portosystemic shunt (TIPS), and ICU treatments. Although the patient had a severe bleeding event during anticoagulation therapy, he recovered well after active treatment and dynamic monitoring of anti-Xa.
UNASSIGNED: Hereditary protein S deficiency caused by a mutation in the PROS1 gene is the genetic basis of this patient, and Enoxaparin Sodium and rivaroxaban have been shown to be highly effective.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. The primary objective of this study was to identify the major pathogenic mutations in a Chinese family with FH.
METHODS: Whole-genome sequencing (WGS) was used to identify variants of FH-related genes, including low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). Bioinformatics software was used to predict signal peptides, transmembrane structures, and spatial construction information of the mutated sequences. Western blotting was performed on the mutant protein to determine the presence of the major structural domains of the LDLR. The PCSK9 and APOB genes were screened and analyzed. Moreover, the proband and his brother were treated with a PCSK9 inhibitor for 1 year, and the effect of the treatment on lipid levels was assessed.
RESULTS: WGS revealed two potentially pathogenic mutations in the LDLR gene. One was a novel mutation, c.497delinsGGATCCCCCAGCTGCATCCCCCAG (p. Ala166fs), and the other was a known pathogenic mutation, c.2054C>T (p. Pro685Leu). Bioinformatics prediction and in vitro experiments revealed that the novel mutation could not be expressed on the cell membrane. Numerous gene variants were identified in the APOB gene that may have a significant impact on the family members with FH. Thus, it is suggested that the severe manifestation of FH in the proband primarily resulted from the cumulative genetic effects of variants in both LDLR and APOB. However, a subsequent study indicated that treatment with a PCSK9 inhibitor (Evolocumab) did not significantly reduce the blood lipid levels in the proband or his brother.
CONCLUSIONS: The cumulative effect of LDLR and APOB variants was the primary cause of elevated blood lipid levels in this family. However, PCSK9 inhibitor therapy did not appear to be beneficial for the proband. This study emphasizes the importance of genetic testing in determining the most suitable treatment options for patients with FH.

OBJECTIVE: Distant metastasis remains the main cause of death in breast cancer. Breast cancer risk is strongly influenced by pathogenic mutation.This study was designed to develop a multiple-feature model using clinicopathological and imaging characteristics adding pathogenic mutations associated signs to predict recurrence or metastasis in breast cancers in high familial risk women.
METHODS: Genetic testing for breast-related gene mutations was performed in 54 patients with breast cancers. Breast MRI findings were retrospectively evaluated in 64 tumors of the 54 patients. The relationship between pathogenic mutation, clinicopathological and radiologic features was examined. The disease recurrence or metastasis were estimated. Multiple logistic regression analyses were performed to identify independent factors of pathogenic mutation and disease recurrence or metastasis. Based on significant factors from the regression models, a multivariate logistic regression was adopted to establish two models for predicting disease recurrence or metastasis in breast cancer using R software.
RESULTS: Of the 64 tumors in 54 patients, 17 tumors had pathogenic mutations and 47 tumors had no pathogenic mutations. The clinicopathogenic and imaging features associated with pathogenic mutation included six signs: biologic features (p = 0.000), nuclear grade (p = 0.045), breast density (p = 0.005), MRI lesion type (p = 0.000), internal enhancement pattern (p = 0.004), and spiculated margin (p = 0.049). Necrosis within the tumors was the only feature associated with increased disease recurrence or metastasis (p = 0.006). The developed modelIincluding clinico-pathologic and imaging factors showed good discrimination in predicting disease recurrence or metastasis. Comprehensive model II, which included parts of modelIand pathogenic mutations significantly associated signs, showed significantly more sensitivity and specificity for predicting disease recurrence or metastasis compared to Model I.
CONCLUSIONS: The incorporation of pathogenic mutations associated imaging and clinicopathological parameters significantly improved the sensitivity and specificity in predicting disease recurrence or metastasis. The constructed multi-feature fusion model may guide the implementation of prophylactic treatment for breast cancers at high familial risk women.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by motile ciliary dysfunction and impaired ultrastructure. Despite numerous studies, the genetic basis for about 30% of PCD cases remains to be elucidated. Here, we present the identification and functional analysis of two novel mutations in the gene encoding coiled-coil domain-containing protein 40 (CCDC40), which are found in a familial case of PCD. These novel CCDC40 mutations, NM_017950.4: c.2236-2delA and c.2042_2046delTCACA, NP_060420.2: p.(Ile681fs), were identified by whole-exome sequencing (WES). Sanger sequencing was then performed to confirm the WES results and determine the CCDC40 gene sequences of the proband\'s parents. The c.2042_2046delTCACA mutation disrupts the reading frame of the protein and is therefore predicted to produce a non-functional protein. Using a minigene assay with the pcDNA3.1(+) plasmid, we further investigated the potential pathogenic effects of the c.2236-2delA mutation and found that this mutation leads to formation of a truncated protein via splicing disruption. Thus, in summary, we identified two mutations of the CCDC40 gene that can be considered pathogenic compound heterozygous mutations in a case of familial PCD, thereby expanding the known mutational spectrum of the CCDC40 gene in this disease.

Diabetic retinopathy (DR) is a common complication and the leading cause of blindness in patients with type 2 diabetes. DR has been shown to be closely correlated with blood glucose levels and the duration of diabetes. However, the onset and progression of DR also display clinical heterogeneity. We applied whole-exome sequencing and RNA-seq approaches to study the gene mutation and transcription profiles in three groups of diabetic patients with extreme clinical phenotypes in DR onset, timing, and disease progression, aiming to identify genetic variants that may play roles in the pathogenesis of DR. We identified 23 putatively pathogenic genes, and ingenuity pathway analysis of these mutated genes reveals their functional association with glucose metabolism, diabetic complications, neural system activity, and dysregulated immune responses. In addition, ten potentially protective genes were also proposed. These findings shed light on the mechanisms underlying the pathogenesis of DR and may provide potential targets for developing new strategies to combat DR.

Osteogenesis imperfecta (OI) is a rare, heterogeneous, genetic disorder characterized by bone fragility and recurrent fractures. Bisphosphonates (BPs) are the most commonly used medications for OI, but their efficacy has great variability.
We investigated the relationship of pathogenic gene mutations and responses to zoledronic acid (ZOL) in a large cohort of children with OI.
Children with OI who received ZOL treatment were included and were followed up for at least 1 year. Bone mineral density (BMD) and serum levels of β-isomerized carboxy-telopeptide of type I collagen (β-CTX, bone resorption marker) were measured at baseline and during follow-up. Causative mutations of OI were identified using next-generation sequencing and Sanger sequencing.
201 children with OI were included. They had initiated ZOL treatment at a median age of 5 years, with mutations identified in 11 genes. After 3 years of treatment, the increase in femoral neck BMD Z-score in patients with OI with autosomal dominant (AD) inheritance was greater than that in patients with autosomal recessive or X-linked inheritance (non-AD) (4.5 ± 2.9 vs 2.0 ± 1.0, P < .001). Collagen structural defects were negatively correlated with the increase in femoral neck BMD Z-score. Patients with collagen structural defects had higher incidence of new fractures (35.1% vs 18.4%, relative risk 0.52, P = .044) and less decline in β-CTX level than those with collagen quantitative reduction. Increase in lumbar spine BMD and change in height Z-score was not associated with the genotype of children with OI.
Patients with OI with non-AD inheritance or with pathogenic mutations leading to collagen structural defects may have relatively poor responses to ZOL treatment, which is possibly associated with their more severe phenotypes. New therapeutic agents are worth developing in these patients.

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disease characterized by disorders of sex development, commonly caused by mutations of the androgen receptor (AR) gene. Herein, we identified a novel hemizygous mutation (c.2118T > A, p. Asn706Lys) of AR resulting in complete androgen insensitivity syndrome (CAIS) in twins. This missense mutation contributed to significantly decreased mRNA transcription and protein expression. In addition, structure model analysis showed that Asn706Lys resulted in loss of hydrogen bond with Asp891 and reduced protein stability. Furthermore, the mutant AR failed to bind to ligand due to the loss of hydrogen bond with dihydrotestosterone (DHT). This disrupted the translocation of AR protein from cytoplasm to nucleus after hormone stimulation. Our findings firstly demonstrated the novel mutation of c.2118T > A in AR directly caused CAIS. This contributed to expanding the AR mutational spectrum and revealed the pathogenic mechanism of AIS, as well as facilitating precise diagnosis and genetic counseling.

PTPN2 is an important protein tyrosine phosphatase (PTP) that plays a key role in cell signaling. Deletions or inactivating mutations of PTPN2 have been described in different pathologies and underline its critical role in hematopoiesis, autoimmunity, and inflammation. Surprisingly, despite the major pathophysiological implications of PTPN2, the structural analysis of this PTP and notably of its pathogenic mutants remains poorly documented. Contrary to other human PTP enzymes, to date, only one structure of PTPN2 (wild-type form) has been reported. Here, we report the first crystal structure of a pathogenic mutant of PTPN2 (Cys216Gly) that causes an autoimmune enteropathy. We show in particular that this mutant adopts a classical PTP fold. More importantly, albeit inactive, the mutant retains its ability to bind substrates and to adopt the characteristic catalytically competent closed form of PTP enzymes. This novel PTPN2 structure may serve as a new tool to better understand PTP structures and the structural impacts of pathogenic mutations. Moreover, the C216G PTPN2 structure could also be helpful to design specific ligands/inhibitors.

UNASSIGNED: Global developmental delay has markedly high phenotypic and genetic heterogeneity, and is a great challenge for clinical diagnosis. Hypotonia, ataxia, and delayed development syndrome (HADDS), first reported in 2017, is one type of global development delay. The aim of the present study was to investigate the genetic etiology of a Chinese boy with global developmental delay.
UNASSIGNED: We combined clinical and imaging phenotyping with trio whole-exome sequencing and Sanger sequencing to the patient and his clinically unaffected parents. A luciferase reporter and immunofluorescence were performed to detect the effect of mutation on transcriptional activity and subcellular localization.
UNASSIGNED: The patient presented with several previously unreported symptoms in the patients with HADDS, including hemangiomas, mild hearing abnormalities and tracheomalacia. A novel EBF3 c.589A > G missense mutation (p.Asn197Asp, p.N197D) was identified in the patient but not in his parents. By constructing the plasmid and transfecting HEK293T cells, EBF3-N197D mutant showed impaired activation of luciferase reporter expression of the p21 promoter, and the mutant affected its entry into the nucleus.
UNASSIGNED: To the best of our knowledge, this is the first report of EBF3 pathogenic mutation which associated with HADDS in the Chinese population. Our results expand the phenotypes and pathogenic mutation spectrum of HADDS, thus potentially facilitating the clinical diagnosis and genetic counseling of HADDS patients.

OBJECTIVE: Mutations in hereditary breast cancer genes play an important role in the risk for cancer.
METHODS: Cancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome.
RESULTS: A total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001).
CONCLUSIONS: Hereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.