Gesehen am 24.04.2020 ; Advance online publication: 29 June 2017
Child; Child, Preschool; DNA Mutational Analysis; Female; Forkhead Transcription Factors; Genetic Association Studies; Genetic Variation; Genotype; Humans; Magnetic Resonance Imaging; Male; Nerve Tissue Proteins; Phenotype; Polymorphism, Single Nucleotide; Rett Syndrome
Purpose: The study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants. Methods: We compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test. Results: Among the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1. Conclusions: These data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.
Genetics in medicine Amsterdam : Elsevier, 1998 20(2018), 1, Seite 98-108 Online-Ressource
von Michael Alber ; Vera M. Kalscheuer ; Elysa Marco ; Elliot Sherr ; Gaetan Lesca ; Marianne Till ; Gyri Gradek ; Antje Wiesener ; Christoph Korenke ; Sandra Mercier ; Felicitas Becker ; Toshiyuki Yamamoto ; Stephen W. Scherer ; Christian R. Marshall ; Susan Walker ; Usha R. Dutta ; Ashwin B. Dalal ; Vanessa Suckow ; Payman Jamali ; Kimia Kahrizi ; Hossein Najmabadi ; Berge A. Minassian
1-deoxy-sphingolipids; Charcot-Marie-Tooth disease; hereditary neuropathy; next generation sequencing; small fiber neuropathy
Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty-four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations.
Journal of neurochemistry Oxford : Wiley-Blackwell, 1956 143(2017), 5, Seite 507-522 Online-Ressource
2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more comprehensive view on this disease, we have collected clinical and biochemical data as well as information on ACAT1 mutations of 32 patients from 12 metabolic centers in five countries. Patients were between 23months and 27years old, more than half of them were offspring of a consanguineous union. 63% of the study participants presented with a metabolic decompensation while most others were identified via newborn screening or family studies. In symptomatic patients, age at manifestation ranged between 5months and 6.8years. Only 7% developed a major mental disability while the vast majority was cognitively normal. More than one third of the identified mutations in ACAT1 are intronic mutations which are expected to disturb splicing. We identified several novel mutations but, in agreement with previous reports, no clear genotype-phenotype correlation could be found. Our study underlines that the prognosis in MAT deficiency is good and MAT deficient individuals may remain asymptomatic, if diagnosed early and preventive measures are applied.
Molecular genetics and metabolism Orlando, Fla. : Academic Press, 1998 121(2017), 1/2, Seite 67-75 Online-Ressource
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