heterozygous mutation
Recently Published Documents

Abstract Background: Over 100 mutations in the SRD5A2 gene have been identified in subjects with 46,XY disorder of sex development (DSD). Exploration of SRD5A2 mutations and elucidation of the molecular mechanisms behind their effects should reveal the functions of the domains of the 5α-reductase 2 enzyme and identify the cause of 46,XY DSD. Previously, we reported a novel compound heterozygous p.Q6X/p.H232R mutation of the SRD5A2 gene in a case with 46,XY DSD. Whether the compound heterozygous p.Q6X/p.H232R mutation in this gene causes 46,XY DSD requires further exploration. Results: To clarify the cause of 46,XY DSD in the affected family focused on here, SRD5A2 sequencing was performed. Heterozygous p.H232R mutation was identified in the proband’s father, so we concluded that this mutation originated from the paternal side of the family and did not cause 46,XY DSD. Meanwhile, heterozygous p.Q6X mutation was identified in the proband’s mother, maternal uncle, and maternal grandfather, indicating that this mutation originated from maternal side of the family and did not cause 46,XY DSD. To clarify the effect of the p.H232R mutation in SRD5A2 on dihydrotestosterone (DHT) production, p.H232R mutant SRD5A2 plasmids were transfected into HEK293 cells. LC-MS indicated that DHT production decreased compared with that in cells transfected with wild-type SRD5A2.Conclusions: Our findings confirmed that the compound heterozygous p.Q6X/p.H232R mutation in the SRD5A2 gene is the cause of 46,XY DSD. p.H232R mutation reduced DHT production while attenuating the catalytic efficiency of the 5α-reductase 2 enzyme.

Abstract Background: Early-onset Alzheimer's disease is defined as Parkinson's disease that begins at an age of 65 or younger. Currently, among the reports on early-onset Alzheimer's disease related genes, mutations of APP, PSEN1 and PSEN2 genes are relatively common, However, the mutation of MAPT P301L causes early-onset Alzheimer's disease, which has not been reported so far. Case report: We have found a clinical case of a 30-year-old male who suddenly developed cognitive impairment and progressed rapidly within 2 years, leaving him unable to take care of himself. The patient underwent examinations of blood and cerebrospinal fluid routine, biochemistry and immunoassay, as well as imaging examinations of MRI, FDGPET and PIBPET. PIB-PET indicated diffuse heterogeneous radionuclivity in cerebral cortex, and positive PIB imaging was considered. Sequencing results suggested that there was a heterozygous mutation in the MAPT gene of the patient, which was located in Chr17-44087755, and c.902C>T. Conclusion: We speculated that EOAD of this patient may be related to the P301L mutation on MAPT.

Abstract Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disease caused by gain-of-function mutations in the NLRP3 gene, with a genotype-phenotype correlation. The clinical presentation of each mutation has been previously studied. However, very few studies have reported on the clinical characteristics and treatment effectiveness across different generations within a family with the same mutation. A detailed investigation of family members of patients with CAPS may help in the appropriate diagnosis and treatment of undiagnosed CAPS. Herein, we report a 2-year-old boy (proband), his father, and his grandmother who presented with several symptoms of CAPS, such as persistently positive inflammatory reactions and hearing impairment. All three patients had the same pathogenic mutation in the NLRP3 gene (c.1049C>T (p.Thr350Met) heterozygous mutation) and were diagnosed with CAPS. With canakinumab treatment, the laboratory data of all three patients improved, the proband and father’s skin rash disappeared, and his grandmother’s arthropathy improved. The proband’s hearing also showed slight improvement, but not in his father or grandmother. Among the various non-specific symptoms associated with CAPS, chronic ocular hyperemia is a finding that can be easily identified by non-ophthalmologists. Diagnosis of CAPS should be considered when eye symptoms are present in a combination of hyperinflammatory response, arthropathy, or skin symptoms. Thorough family history records, physical examinations, and close collaboration between pediatricians and adult rheumatologists are important for prompt diagnosis and appropriate treatment of inherited autoinflammatory diseases.

Many proteins are causative for inherited partial lipodystrophies, including lamins, the essential constituents of the nuclear envelope scaffold called the lamina. By performing high throughput sequencing on a panel of genes involved in lipodystrophies, we identified a heterozygous mutation in LMNB2 gene (c.700C > T p.(Arg234Trp)) in a female patient presenting early onset type II diabetes, hypertriglyceridemia, and android fat distribution. This mutation is rare in the general population (frequency 0.013% in GnomAD) and was predicted pathogenic by a set of pathogenicity prediction software. Patient-derived fibroblasts showed nuclear shape abnormalities and premature senescence features, which are two typical cellular phenotypes associated with laminopathies. Moreover, we observed an atypical aggregation of lamin B2 in nucleoplasm, which co-distributes with emerin and lamin A/C, along with an abnormal distribution of lamin A/C at the nuclear envelope. Finally, reducing lamin B2 expression level by siRNA targeted toward LMNB2 transcripts resulted in decreased nuclear anomalies and senescence-associated beta-galactosidase, suggesting a role of the mutated protein in the occurrence of the observed cellular phenotype. Altogether, these results suggest that mutations in lamin B2 could produce premature senescence and partial lipodystrophy features as observed with certain mutants of lamin A/C.

Background: Hypertrophic cardiomyopathy (HCM) is the second most common cardiomyopathy in childhood with a life-threatening risk. Implantable cardioverter-defibrillator (ICD) placement is recommended for early prevention if there are two or more clinical risk factors. Pediatric patients with HCM are at a higher risk of sudden cardiac death (SCD), but there are limited reports on indications for ICD implantation in children. Herein we describe the case of Myh7 mutation-induced HCM and cardiac arrest in a patient and evaluated information originating from genetic background to guide ICD administration.Case Presentation: The patient was a girl aged 7 years and 8 months who had been diagnosed with cardiomyopathy in utero 8 years prior. She had had recurrent cardiac arrests within the last 4 years. Electrocardiography indicated abnormalities in conduction, and ST segment changes. Echocardiography indicated significant left ventricular hypertrophy and hypertrophic systolic interventricular septum. Cardiac magnetic resonance imaging depicted general heart enlargement with hypertrophy, and delayed enhancement in myocardium with perfusion defect was also evident. Whole exon sequencing identified a de novo c.2723T>C (p.L908P) heterozygous mutation in the MYH7 gene. MYH7 p.L908P predicted unstable protein structure and impaired function. The patient was scheduled for ICD implantation. There were no complications after ICD implantation, and she was discharged from hospital on the 10th day. Regular oral beta-blockers, amiodarone, spironolactone, and enalapril were administered, and she was required to attend hospital regularly for follow-up. During follow-up there were no cardiac arrests. Literature review of clinical prognoses associated with genetic mutations of MYH7, MYBPC3, TNNI3, TNNT2, and TPM1 in pediatric HCM patients with and without ICD implantation indicated that they were totally differently. Previous reports also indicated that gene mutations predicted earlier onset of cardiac hypertrophy, and increase likelihood of SCD.Conclusion: Variant burden and variant type contribute to the risk of adverse events in pediatric HCM. Early recognition and intervention are vital in children. Gene mutation could be considered an indication for early ICD placement during standard risk stratification of HCM patients. Whether this extends to the majority of pediatric patients requires further investigation.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is an autosomal dominant primary immunodeficiency caused by acquired gene function mutation (GOF). APDS has a variety of clinical phenotypes, particularly recurrent respiratory infections and lymphoproliferation. Here we report a pediatric patient with APDS who presented with recurrent respiratory infections, lymphoproliferation, hepatosplenomegaly, bronchoscopy suggesting numerous nodular protrusions in the airways and a decrease in both T and B lymphocytes, and progression to plasmablastic lymphoma (PBL) after 1 year. Whole exome sequencing revealed a heterozygous mutation in the PIK3CD gene (c.3061 G>A p.E1021K). This is the first reported case of APDS combined with PBL and pediatricians should follow up patients with APDS regularly to be alert for secondary tumours.

Abstract Context Patients with aggrecan (ACAN) deficiency present with dominantly inherited short stature, often with advanced skeletal maturation and premature growth cessation. There is a paucity of information on the effects of growth-promoting interventions. Objective The aim of this study was to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) therapy on linear growth in children with ACAN deficiency. Design and Setting Open-label, single-arm, prospective study at Cincinnati Children’s Hospital Medical Center. Patients Ten treatment-naïve patients were recruited. Inclusion criteria were: a confirmed heterozygous mutation in ACAN, age ≥ 2 years, pre-pubertal, bone age (BA) ≥ chronological age (CA), and normal IGF-I concentration. Intervention Treatment with rhGH (50 mcg/kg/day) over one year. Main Outcome Measure(s) Main outcomes measured were height velocity (HV) and change in (Δ) height SD (HtSDS). Results Ten patients (six females) were enrolled with median CA of 5.6 yrs (range 2.4 to 9.7). Baseline median HtSDS was -2.5 (range -4.3 to -1.1). Median baseline BA was 6.9 yrs (range 2.5 to 10.0), with median BA/CA of 1.2 (range 0.9 to 1.5). Median pre-treatment HV was 5.2 cm/y (range 3.8 to 7.1), increased to 8.3 cm/y (range 7.3 to 11.2) after one year of therapy (p=0.004). Median ΔHtSDS after one year was +0.62 (range +0.35 to +1.39) (p=0.002). Skeletal maturation did not advance inappropriately (median Δ BA/CA -0.1, p=0.09). No adverse events related to rhGH were observed. Conclusion Treatment with rhGH improved linear growth in a cohort of patients with short stature due to ACAN deficiency.