Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

• MeSH
• Deep Learning * MeSH
• Child MeSH
• Adult MeSH
• Phenotype * MeSH
• Genetic Variation MeSH
• Genetic Association Studies MeSH
• Genomics methods   MeSH
• Thyroid Hormones metabolism   genetics   MeSH
• Humans MeSH
• X-Linked Intellectual Disability genetics   metabolism   MeSH
• Adolescent MeSH
• Loss of Function Mutation MeSH
• Child, Preschool MeSH
• Monocarboxylic Acid Transporters * genetics   metabolism   MeSH
• Severity of Illness Index MeSH
• Muscular Atrophy genetics   metabolism   pathology   MeSH
• Muscle Hypotonia genetics   metabolism   MeSH
• Symporters * genetics   metabolism   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Cullin 4B (CUL4B), lysosomal-associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities. Heterozygous CS females are clinically asymptomatic. LAMP2 mutations cause Danon disease (DD). Cardiomyopathy is a dominant feature of DD present in both males and heterozygous females. No monogenic phenotypes have been associated with mutations in ATP1B4, TMEM255A, and ZBTB33 genes. To facilitate diagnostics and counseling in CS and DD families, we present a female DD patient with a de novo Alu-mediated Xq24 rearrangement causing a deletion encompassing CUL4B, LAMP2, and also the other three neighboring genes. Typical to females heterozygous for CUL4B mutations, the patient was CS asymptomatic, however, presented with extremely skewed X-chromosome inactivation (XCI) ratios in peripheral white blood cells. As a result of the likely selection against CUL4B deficient clones, only minimal populations (~3%) of LAMP2 deficient leukocytes were identified by flow cytometry. On the contrary, myocardial LAMP2 protein expression suggested random XCI. We demonstrate that contiguous CUL4B and LAMP2 loss-of-function copy number variations occur and speculate that male patients carrying similar defects could present with features of both CS and DD.

• MeSH
• Chromosome Deletion MeSH
• Adult MeSH
• Alu Elements genetics   MeSH
• Exons genetics   MeSH
• Glycogen Storage Disease Type IIb diagnosis   genetics   physiopathology   MeSH
• X Chromosome Inactivation genetics   MeSH
• Cardiomyopathies genetics   physiopathology   MeSH
• Cullin Proteins genetics   MeSH
• Humans MeSH
• Lysosomal-Associated Membrane Protein 2 genetics   MeSH
• X-Linked Intellectual Disability genetics   physiopathology   MeSH
• Loss of Function Mutation genetics   MeSH
• Myocardium metabolism   MeSH
• Sodium-Potassium-Exchanging ATPase genetics   MeSH
• Transcription Factors genetics   MeSH
• DNA Copy Number Variations genetics   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

MEHMO syndrome is a rare X-linked syndrome characterized by Mental retardation, Epilepsy, Hypogenitalism, Microcephaly, and Obesity associated with the defect of protein synthesis caused by the EIF2S3 gene mutations. We hypothesized that the defect in protein synthesis could have an impact on the immune system. We describe immunologic phenotype and possible treatment outcomes in patient with MEHMO syndrome carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. The proband (currently 9-year-old boy) had normal IgG and IgM levels, but had frequent respiratory and urinary tract infections. On subcutaneous immunoglobulin therapy achieving supra-physiological IgG levels the frequency of infections significantly decreased in Poisson regression by 54.5 % (CI 33.2-89.7, p=0.017). The MEHMO patient had had frequent acute infections despite normal IgG and IgM serum levels and responded well to the immunoglobulin treatment.

• MeSH
• Child MeSH
• Epilepsy drug therapy   genetics   immunology   pathology   MeSH
• Eukaryotic Initiation Factor-2 genetics   MeSH
• Phenotype MeSH
• Hypogonadism drug therapy   genetics   immunology   pathology   MeSH
• Humans MeSH
• X-Linked Intellectual Disability drug therapy   genetics   immunology   pathology   MeSH
• Microcephaly drug therapy   genetics   immunology   pathology   MeSH
• Mutation * MeSH
• Obesity drug therapy   genetics   immunology   pathology   MeSH
• Genitalia abnormalities   immunology   pathology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

• Keywords
• trijodotyrereooctová kyselina, Triac,
• MeSH
• Child MeSH
• Humans MeSH
• X-Linked Intellectual Disability * diagnosis   genetics   therapy   MeSH
• Cerebral Palsy diagnosis   genetics   MeSH
• Monocarboxylic Acid Transporters genetics   MeSH
• Triiodothyronine pharmacokinetics   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.

• MeSH
• Diabetes Mellitus, Type 1 congenital   genetics   MeSH
• Endocrine Glands metabolism   MeSH
• Epilepsy genetics   MeSH
• Eukaryotic Initiation Factor-2 genetics   MeSH
• Phenotype MeSH
• Hypoglycemia congenital   genetics   MeSH
• Hypogonadism genetics   MeSH
• Hypopituitarism congenital   genetics   MeSH
• Humans MeSH
• X-Linked Intellectual Disability genetics   MeSH
• Microcephaly genetics   MeSH
• Infant, Newborn MeSH
• Obesity genetics   MeSH
• Genitalia abnormalities   MeSH
• Frameshift Mutation MeSH
• Transcription Factors MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH

• Keywords
• tetrazomie X chromozomu kariotyp 48 - XXXX,
• MeSH
• Chromosome Aberrations MeSH
• Central Nervous System Cysts diagnosis   MeSH
• Speech-Language Pathology MeSH
• Humans MeSH
• X-Linked Intellectual Disability genetics   MeSH
• Mutation MeSH
• Oxygenators MeSH
• Child Care MeSH
• Child, Preschool MeSH
• Psychomotor Disorders diagnosis   genetics   pathology   rehabilitation   MeSH
• Rehabilitation MeSH
• Schools, Nursery MeSH
• Muscle Hypotonia * diagnosis   genetics   pathology   rehabilitation   MeSH
• Genetic Complementation Test * MeSH
• Tetrasomy * diagnosis   genetics   immunology   pathology   MeSH
• Foot Deformities, Congenital genetics   surgery   MeSH
• Language Development Disorders * diagnosis   genetics   pathology   therapy   MeSH
• Infertility, Female MeSH
• Check Tag
• Humans MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Case Reports MeSH
• Interview MeSH

ECTIVE: Total creatine (tCr) constitutes one of the most prominent signals in human brain MR spectra. A significant decrease in the tCr signal indicates a severe disorder of creatine metabolism. We describe the potential of 1H MR spectroscopy in differential diagnosis of creatine transporter (SLC6A8) deficiency syndrome. MATERIALS AND METHODS: Two siblings, a 7-year-old female presenting with mild psychomotor delay, and a 5-year-old male with severe psychomotor retardation, epilepsy and autistic spectrum of problems including speech delay, underwent MR examination because of suspected creatine deficiency. After the MRI examination, 1H MR spectroscopy using the CSI technique was performed. RESULTS: Metabolic images of N-acetylaspartate, tCr and choline concentrations showed a very low tCr signal in the male, which was approximately three times lower than in his sister (male/female/controls: tCr=1.6/4.6/7.5 mM). Despite creatine supplementation, no improvement in clinical status and tCr concentration in the MR spectra of the male was observed and diagnosis of SLC6A8 deficiency was proposed. Sequence analysis of the SLC6A8 gene revealed a novel pathogenic frameshift mutation c.219delC; p.Asn74ThrfsX23, hemizygous in the male and heterozygous in the female. CONCLUSIONS: The diagnosis of X-linked mental retardation caused by the SLC6A8 deficiency can be independently established by 1H MR spectroscopy.

• MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• DNA Primers genetics   MeSH
• Creatine deficiency   MeSH
• Humans MeSH
• Magnetic Resonance Spectroscopy diagnostic use   methods   MeSH
• Magnetic Resonance Imaging MeSH
• X-Linked Intellectual Disability diagnosis   genetics   metabolism   MeSH
• Brain metabolism   pathology   MeSH
• Child, Preschool MeSH
• Nerve Tissue Proteins genetics   deficiency   MeSH
• Plasma Membrane Neurotransmitter Transport Proteins genetics   deficiency   MeSH
• Base Sequence MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Syndrom fragilního X chromozomu je X vázané dědičné onemocnění projevující se mentální retardací u postižených mužů a lehčí mentální dysfunkcí u postižených žen. Většina nemocných má také poruchy chování včetně hyperaktivity a autismu. Na molekulární úrovni jsou známy 2 rozdílné typy syndromu fragilního X chromozomu: FRAXA a FRAXE. Článek pojednává o klinické a molekulárně-genetické analýze rodiny s výskytem syndromu fragilního X chromozomu typu FRAXE, která zatím v naší literatuře nebyla popsána. U probanda s psychomotorickou retardací byl molekulární analýzou vyloučen syndrom typu FRAXA. Kombinací polymerázové řetězové reakce (PCR) a Southernova blottingu byla zavedena metoda pro detekci syndromu typu FRAXE. Popsaná technika umožňuje určit zvětšení a přibližnou velikost (CCG)n repetice v 5' oblasti FMR2 genu. Bylo zjištěno, že matka probanda je nositelkou mutantní FRAXE alely, kterou předala svému synovi. V souladu s dříve publikovanými údaji byla potvrzena nestabilita (CCG)n repetitivní oblasti FMR2 genu v průběhu přenosu z jedné generace do druhé jak ve smyslu její expanze, tak také její kontrakce. Sdělení poukazuje na důležitost DNA analýzy nejen FMR1 genu (typ FRAXA), ale i FMR2 genu (typ FRAXE) u pacientů s mentální retardací s podezřením na syndrom fragilního X chromozomu.

Fragile X syndrome is X linked inherited disease which manifests with mental retardation at affected males and mild mental dysfunction at affected females. Majority of patients háve also behavioral problems including hyperactivity and autism. There are two different types of fragile X syndrome on the molecular level: FRAXA and FRAXE. Present article deal with clinical and molecular genetics analysis of affected family for the FRAXE type of fragile X syndrome that has not been described in the Czech literatuře yet. First, the FRAXA type of syndrome was excluded by molecular analysis at the proband with psychomotor retardation. Consecutively, a method for detection of the FRAXE type of syndrome was established by combination of polymerase chain reaction (PCR) and Southern blotting. Described technique allows to determine an expansion and approximate size of (CCG)n repeat at the 5' end of the FMR2 gene. It was found that mother of the proband is a carrier of the mutant FRAXE allele which passed to her son. In agreement with previously published results, it was confirmed that the (CCG)n repeat at the FMR2 gene is unstable when passed through one generation to the next. Both, the expansion and the contraction of the (CCG)n repeat was observed at studied family. Our report indicates that not only DNA analysis of FMR1 gene (FRAXA type) but also DNA analysis of FMR2 gene (FRAXE type) is important at patients with mental retardation that are suspected for fragile X syndrome.

• MeSH
• Molecular Diagnostic Techniques MeSH
• Research Support as Topic MeSH
• Humans MeSH
• X-Linked Intellectual Disability genetics   MeSH
• Fragile X Syndrome diagnosis   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Case Reports MeSH