NOTCH3 Variants in Patients with Suspected CADASIL.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease. It is clinically, radiologically, and genetically heterogeneous and is caused by NOTCH3 mutations. Methods: In this study, we analyzed NOTCH3 in 368 patients with suspected CADASIL using next-generation sequencing. The significant variants detected were reported along with the clinical and radiological features of the patients. Results: Heterozygous NOTCH3 changes, mostly missense mutations, were detected in 44 of the 368 patients (~12%). Conclusions: In this single-center study conducted on a large patient group, 30 different variants were detected, 17 of which were novel. CADASIL, which can result in mortality, has a heterogeneous phenotype among individuals in terms of clinical, demographic, and radiological findings regardless of the NOTCH3 variant.

ATP7B Gene Variant Profile Identified by NGS in Wilson's Disease.

Background: Wilson's disease (WD) is a copper metabolism disorder caused by ATP7B gene mutations and shows an autosomal recessive pattern of inheritance. We aimed to contribute to the mutation profile of ATP7B and show demographic and phenotypic differences in this study. Materials and methods: The clinical and demographic characteristics of patients who underwent ATP7B gene sequence analysis using next-generation sequencing were evaluated to improve genotype-phenotype correlation in WD. Results: An uncertain significance (D563N) and seven likely pathogenic (Y532D, Y715Y, T977K, K1028*, E1086K, A1227Pfs*103, and E1242K) variants were identified as associated with WD. Uniparental disomy was detected in one case. Conclusion: Our work expanded the ATP7B variant spectrum and pointed to clinical heterogeneity in ATP7B variants among patients with WD. All symptomatic patients had hepatic involvement and were clinically and/or genetically diagnosed with WD in the pediatric period. T977K, A1003V, H1069Q, E1086K, and N1270S variants were associated with hepatic failure.

Clinical exome sequencing findings in 1589 patients.

Clinical exome sequencing (CES) is important for the diagnosis of Mendelian diseases, which are clinically and etiologically heterogeneous. Sharing of large amounts of CES data associated with clinical findings will increase the accuracy of variant interpretation. We performed a retrospective study to state the diagnostic yield of CES in 1589 patients with a wide phenotypic spectrum. CES was performed using the Sophia Clinical Exome Sequencing Kit with 4493 genes, followed by sequencing on a NextSeq 500 system. The diagnosis rate was 36.8% when only pathogenic and likely pathogenic variants were included. Consanguineous unions and positive family history were associated with a high diagnostic yield. The neurological disease group had the highest number of patients. The groups with high diagnosis rates were ear, eye, and muscle disease groups. Seven candidate genes (EFHC2, HSPB3, FAAH2, ITGB1, GYG2, CD177, and CSTF2T) that are not yet associated with human diseases were identified. Owing to the high diagnostic yield of CES compared with that of other genetic tests, it can be used as a standard diagnostic test in patients with rare genetic disorders that require a wide differential diagnosis, especially in laboratories with limited resources.

Coexistence of Three Different Mutations in a Male Infant: neurofibromatosis Type 1, Progressive Familial Intrahepatic Cholestasis Type 2 and LPIN3.

IntroductionThe coexistence of progressive familial intrahepatic cholestasis type 2, failure to thrive due to an LPIN3 mutation, and stigmata of neonatal neurofibromatosis represents a complex diagnostic challenge. Case report: We present a child with cholestasis requiring hepatic transplantation, explained by the progressive familial intrahepatic cholestasis type 2, failure to thrive could be contributed to by the LPIN3 mutation, and skin findings along with the family history of the patient was due to neurofibromatosis type 1. Conclusion: Our case illustrates the complexities of multiple genetic mutations in a child.

Acquired Thrombotic Thrombocytopenic Purpura in a 5-Year-old Child With Wiskott-Aldrich Syndrome.

Thrombocytopenia is often seen as a laboratory finding during childhood. A supposed idiopathic thrombocytopenic purpura patient who was later diagnosed as Wiskott-Aldrich syndrome (WAS) and developed acquired thrombotic thrombocytopenic purpura (aTTP). Although autoimmune manifestations in WAS described, aTTP was reported just once. Five-year-old-boy was initially brought with cough, bloody stool (diarrhea), oral mucosal bleeding at 12th months of age. Following diagnosed with idiopathic thrombocytopenic purpura and receiving intravenous immunoglobulin, platelet count raised from 20,000 to 50,000/µL. One year after WAS diagnosis by mutation analysis, he presented with complaints of resistant fever, epistaxis, and melena. Hemoglobin decreased from 10 to 5.9 g/dL. Schistocytes in peripheral blood smear and high anti-ADAMTS-13 antibody level indicated development of aTTP.

Newly defined peroxisomal disease with novel ACBD5 mutation.

Peroxisomal disorders are a heterogeneous group of diseases caused by mutations in a large number of genes. One of the genetic disorders known to cause this situation is ACBD5 (Acyl-CoA binding-domain-containing-5) gene mutations that have been described in recent years. Here, we report two siblings with a novel homozygous nonsense variation (c.1297C>T, p.Arg433*) in ACBD5 (NM_145698.4) gene using Clinical Exome Sequencing (Sophia Genetics).

A Novel Homozygous Mutation in the MYO5B Gene Associated With Normal-Gamma-Glutamyl Transferase Progressive Familial Intrahepatic Cholestasis.

The genetic defect of MYO5B is usually associated with microvillus inclusion disease (MVID). MYO5B mutations are one of the rare causes of progressive familial intrahepatic cholestasis (PFIC) with normal/low gamma-glutamyl transferase (GGT). In this report, we discuss the case of a nine-month-old girl with low-GGT cholestasis whose next-generation sequencing (NGS) showed a homozygous splicing variation (c.3045+3A>T) on the MYO5B (NM_001080467) gene, which was a novel mutation. We identified that this mutation had a disease-causing effect in silico analysis.

3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH) Deficiency Cases Diagnosed by Only HIBCH Gene Analysis and Novel Pathogenic Mutation.

OBJECTIVE: 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is a rare metabolic disease of valine metabolism. Only 22 cases of HIBCH deficiency have been reported in the literature. Our algorithm could help in the diagnosis of this disease. METHODS: HIBCH gene analysis was performed in all cases. RESULTS: The common features of our five patients from the same family with a developmental delay, seizures, and neurological regression were the elevation of 3-hydroxy-isobutyryl-carnitine and Leigh-like abnormalities. Unlike other patients in the literature, our patients were diagnosed with HIBCH gene analysis, rather than whole exome sequencing (WES). In all our cases, a missense c.452C>T, p. Ser151Leu homozygous novel pathogenic mutation was detected in the HIBCH gene. CONCLUSION: In cases where HIBCH deficiency is considered in our differential diagnosis algorithm, HIBCH gene analysis, which is cost-effective, should be performed instead of WES, and the number of cases should be increased in the literature.

Patients with cerebrotendinous xanthomatosis diagnosed with diverse multisystem involvement.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by deficiency of sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. This multicenter, cross-sectional descriptive study aimed to document clinical characteristics of CTX patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid (CDCA) treatment. Seven of 11 CTX patients were diagnosed in childhood. Three patients (27%) had neonatal cholestasis, seven (63%) patients had a history of frequent watery defecation started in infantile period, and eight (72.7%) patients had juvenile cataract. Four patients in the adult age group had pyramidal signs and parkinsonism symptoms. The mean Mignarri score at diagnosis was significantly lower in the pediatric patients (267.8 ± 51.4) than in the adult patients (450.0 ± 64.0, p = 0.001). No significant difference was determined between pediatric patients and adult patients regarding plasma cholestanol concentration at diagnosis (p = 0.482). The frequency of defecation decreased with treatment in six children, who had diarrhea at admission. Compared to pretreatment values, patients' body weight and standardized body mass index significantly increased at the 12th month of treatment. In conclusion, Mignarri scores are lower in the pediatric patients than in adult patients since the most determinative signs of the CTX disease are not apparent yet in the childhood. The disease is frequently overlooked in routine practice as the disease presents itself with different clinical combinations both in adults and in children. CTX is potentially a treatable disease; thereby, enhanced awareness is critically important for early diagnosis particularly in children.

A Novel Homozygous Mutation in CYP11A1 Gene is Associated with Severe Adrenal Insufficiency in 46, XX Patient.

BACKGROUND: One of the causes of congenital adrenal insufficiency, a genetically heterogeneous disorder is a mutation in the CYP11A1 gene, which is responsible for the initiation of steriodogenesis by converting cholesterol to pregnenolone. Case: In a now 3 years and 3 months-old girl, adrenal insufficiency was diagnosed in the neonatal period. Clinical exome sequencing for primary adrenal insufficiency revealed a homozygous p.Thr330Met (c.989C>T) variant in the CYP11A1 (NM_000781) gene. Conclusion: Different types of inheritance patterns have been observed in CYP11A1-related adrenal insufficiency cases. We consider our case is an due to an autosomal recessive inheritance.

A Novel Nonsense FMN2 Mutation in Nonsyndromic Autosomal Recessive Intellectual Disability Syndrome.

Introduction Genetic causes of the intellectual disability Nonsyndromic Autosomal-Recessive Intellectual Disability Syndrome (MRT47, MIM 616193) are mutations in the recently described FMN2 (formin 2 gene). Case report: A boy with intellectual disability had a novel homozygous nonsense mutation (c.2245C > T/p.Gln749*) leading to a premature stop codon in exon 6 of the FMN2 (NM_001305424) gene detected by Clinical Exome Sequencing (CES). Conclusion: Clinical features of a patient with a novel nonsense FMN2 mutation is presented. We urge the change in the OMIM nomenclature from Mental Retardation, Autosomal Recessive 47 (MRT47, MIM 616193) to 'Nonsyndromic Autosomal-Recessive Intellectual Disability Syndrome'.

First Infertile Case with CSTF2TGene Mutation.

Male infertility is multifactorial and presents with heterogeneous phenotypic features. Genetic factors are responsible for up to 15% of the male infertility cases. Loss of the Cstf2t gene in male mice results in infertility. No disease-associated mutations have been described for this gene in infertile men. Here, we report a patient diagnosed with infertility in whom a homozygous nonsense mutation in the CSTF2T gene was detected by clinical exome sequencing. This case is the first description of an infertile patient who has a homozygous CSTF2T mutation.

The role of genetic mutations in intrahepatic cholestasis of pregnancy.

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder of pregnancy characterized by pruritus, elevated liver enzymes and fasting serum bile acids. Genetic predisposition has been suggested to play a role in its etiology and mutations in the ATP8B1(OMIM ∗602397) (FIC1), ABCB11(OMIM ∗603201) (BSEP), and ABCB4(OMIM ∗171060) (MDR3) genes have been implicated. In the present study, we aimed to investigate the possible role of ATP8B1, ABCB11, and ABCB4 gene mutations in the patients with ICP. MATERIALS AND METHODS: A total of 25 patients who were diagnosed with ICP were included in the study. Genetic test results and mutation status of the patients as assessed by the next-generation sequencing technology were retrospectively retrieved from the hospital database. RESULTS: Of all patients, significant alterations in the ATP8B1 (n = 2), ABCB11 (n = 1), and ABCB4 (n = 7) genes were observed in 10 patients using the molecular analysis testing. All these alterations were heterozygous. Of these alterations, four were reported in the literature previously, while six were not. Using the in-silico parameters, there was a pathogenic alteration in the ABCB4 gene in one patient, while there was no clinically relevant alteration in the other gene mutations in the remaining nine patients. CONCLUSION: Considering the fact that the alterations were compatible with clinical presentations of the ICP patients and the incidence of these mutations is low in the general population, we believe that our study results are clinically relevant. Further molecular genetic tests in ICP patients and functional studies supporting the results would shed light into the clinical importance of these alterations.

Two patients with glutaric aciduria type 3: a novel mutation and brain magnetic resonance imaging findings.

BACKGROUND: Glutaric Aciduria Type 3 (GA-3) is a rare metabolic disease which is inherited autosomal recessively and characterized by isolated glutaric acid excretion. To date, a limited number of cases have been reported in the literature. We present two patients with GA3 who were diagnosed with the isolated increased level of glutaric acid in urine. CASE: Glutaric aciduria type 1 and type 2 were excluded by genetic analysis and other laboratory and clinical findings. One of our patients had a homozygous mutation p.Arg322Trp (c.964C > T) of SUGCT (NM_001193311) gene. To the best of our knowledge this mutation has not been reported in the literature previously. Symmetrical periventricular and deep cerebral white matter abnormalities were detected on his brain magnetic resonance imaging (MRI). CONCLUSION: We present two patients with GA-3 and a novel mutation in the SUGCT gene. Our findings expand the spectrum of causative mutations and clinical findings in GA-3.

Two different missense mutations of PEX genes in two similar patients with severe Zellweger syndrome: an argument on the genotype-phenotype correlation.

Background Peroxisomal biogenesis disorders (PBDs) include a miscellaneous group of diseases which cause serious multisystem disease. Mutations of 13 different PEX genes lead to PBDs including Zellweger syndrome (ZS). Different types of mutations of PEX1 and PEX10 genes are correlated with broad-range phenotypes of PBDs. Case presentation Patient 1 is a 4-month-old boy who was affected by myoclonic seizures, poor oral feeding since birth. The patient was hypotonic and had hepatosplenomegaly. Patient 2 is a 2-month-old boy who presented with decreased movement, severe hypotonia and failure to thrive. The laboratory studies of the patients revealed increased plasma very-long-chain fatty acids (VLCFAs). The genetic analyses of patient 1 demonstrated the first homozygous missense mutation in the PEX10 gene. A novel homozygous missense mutation was found in the PEX1 gene in patient 2. Conclusions This report highlights that the detected homozygous missense mutations of PEX10 and PEX1 genes and the substitutions of specific amino acids lead to the severe form of PBDs.