New Syndromes
Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy
The Annals of Neurology published a study of two unrelated, three-generation families with mild skeletal myopathy associated with prominent and consistent tremor. Two novel missense mutations in MYBPC1 (p.E248K in family 1 and p.Y247H in family 2) were identified and shown to segregate perfectly with the myopathy/tremor phenotype in the respective families. MYBPC1 encodes slow myosin binding protein-C (sMyBP-C), a modular sarcomeric protein playing structural and regulatory roles through its dynamic interaction with actin and myosin filaments.This study shown that two novel missense mutations in MYBPC1 are associated with a dominant, mild skeletal myopathy invariably associated with a distinctive tremor.
Ann Neurol. 2019 Jul;86(1):129-142
De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment
A study published in the European Journal of Human Genetics reported seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom four novel, de novo missense variants in the N-terminal half of HK1 were identified. Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis.
Eur J Hum Genet. 2019 Jul;27(7):1081-1089
Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features
The American Journal of Medical Genetics published a study of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. A number of de novo alterations in the KDM6B gene were identified via whole exome sequencing. Lysine‐specific demethylase 6B (KDM6B) demethylates trimethylated lysine‐27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders.
Am J Med Genet A. 2019 Jul;179(7):1276-1286
A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities
A study published in Brain described a large consanguineous pedigree with a complex developmental disorder associated with wide-ranging symptoms, including mental retardation, speech and language impairment and other neurological, psychiatric, skeletal and cardiac abnormalities. A novel nonsynonymous homozygous mutation in exon 9 of the WIPI2 (WD-repeat protein interacting with phosphoinositide 2) gene, playing a critical role in autophagy, was identified in two affected individuals from two separate branches of the extended pedigree.
Brain. 2019 May 1;142(5):1242-1254
Actininopathy: A new muscular dystrophy caused by ACTN2dominant mutations.
A study published in the Annals of Neurology described 4 families (3 from Spain and 1 from Sweden) suffering from an autosomal dominant distal myopathy with ACTN2dominant mutations. Affected members showed adult onset asymmetric distal muscle weakness with initial involvement of ankle dorsiflexion later progressing also to proximal limb muscles. Actininopathy is thus a new genetically determined distal myopathy.
Ann Neurol. 2019 Jun;85(6):899-906
Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype
A recent study published in the Proceedings of the National Academy of Sciences of the United States of America identified two patients with defective serum transferrin glycosylation and mutations in the MAGT1 gene. These patients present with a phenotype that is mainly characterized by intellectual and developmental disability. MAGT1 has been described to be a subunit of the oligosaccharyltransferase complex and more specifically of the STT3B complex. However, it was also claimed that MAGT1 is a magnesium transporter. So far, patients with mutations in MAGT1 were linked to a primary immunodeficiency, characterized by chronic EBV infections attributed to a Mg2+ homeostasis defect. This study showed that MAGT1-congenital disorders of glycosylation are associated with two different clinical phenotypes caused by defects in glycosylation.
Proc Natl Acad Sci U S A. 2019 May 14;116(20):9865-9870
Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus
A study published in Brain described a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. A homozygous mutation in the aryl hydrocarbon receptor (AHR) gene was identified. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. The researchers propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.
Brain. 2019 Jun 1;142(6):1528-1534
Biallelic GALM pathogenic variants cause a novel type of galactosemia
A new study publihed in the Genetics in Medicine published identified eight patients with unexplained congenital galactosemia with biallelic variants in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. The study showed that biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.
Genet Med. 2019 Jun;21(6):1286-1294
- To read more about “Galactosemia”
Homozygous variants in the gene SCAPER cause syndromic intellectual disability.
A new study published in the American Journal of Medical Genetics reported 10 patients from four families with intellectual disability, retinis pigmentosa, and additional dysmorphic features carrying homozygous variants in SCAPER. The variants found comprise frameshift, nonsense, and missense variants as well as an intragenic homozygous deletion, which spans SCAPER exons 15 and 16 and introduces a frameshift and a premature stop codon. The study supported the role of SCAPER variants in the pathogenesis of ID and RP, expands the variant spectrum and highlights the need for functional studies concerning the role of SCAPER during brain development and function.
Am J Med Genet A. 2019 Jul;179(7):1214-1225
Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24
A study published in the Human Molecular Genetics identified homozygous mutations in KLHL24 in two consanguineous families with hypertrophic cardiomyopathy. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. The study revealed a crucial role for KLHL24 in cardiac development and function.
Hum Mol Genet. 2019 Jun 1;28(11):1919-1929
- To read more about “Hypertrophic cardiomyopathy”
HNRNPR variants that impair homeobox gene expression drive developmental disorders in humans
A new study published in the American Journal of Human Genetic reported four unrelated individuals who have truncating or missense variants in the same C-terminal region of HNRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, that are considered fundamental regulators of embryonic and gonad development. This study established an essential role for HNRNPR in human development.
Am J Hum Genet. 2019 Jun 6;104(6):1040-1059
Bi-allelic variants in DYNC1I2 cause syndromic microcephaly with intellectual disability, cerebral malformations, and dysmorphic facial features
A study published in The American Journal of Human Genetics identified five individuals from three independent pedigrees with likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. The study indicated that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.
Am J Hum Genet. 2019 Jun 6;104(6):1073-1087
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