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1.
Eur J Med Genet ; 66(10): 104842, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37709012

ABSTRACT

Lamellar ichthyosis (LI) is an autosomal recessive congenital ichthyosis characterized by generalized dry skin and severe scaling. It is caused by biallelic mutations in the TGM1 gene, however molecular data from non-Caucasian populations are limited. Results of genetic-molecular analysis of a group of LI pedigrees originating from two close small populations from south Mexico are presented. LI affected individuals belonging to 9 apparently unrelated families were studied. Exome sequencing or Sanger sequencing in probands from each family was carried out. Furthermore, DNA from 294 unaffected subjects from one of the communities were Sanger sequenced to determine the carrier frequency of the c.427C > T TGM1 variant. Five different TGM1 pathogenic variants, either in homozygous or in compound heterozygous state, were demonstrated in affected subjects. The two most common variants were c.427C > T (p.Arg143Cys) and c.1159+1G > T. A novel c.1645+1G > T TGM1 pathogenic allele was recognized. Carrier frequency analysis identified a total of 23 individuals heterozygous for the c.427C > T variant, predicting a prevalence of 78 carriers per 1000 inhabitants in the community. A high TGM1 allelic heterogeneity with 5 different LI-causing alleles in a limited geographic area was demonstrated. While the occurrence of homozygosity for a founder mutation is expected in small populations with high frequency of a particular autosomal recessive disorder, the occurrence of multiple pathogenic alleles has been previously described, a situation known as the Reúnion paradox. Our results expand the current knowledge of the mutational spectrum of TGM1-linked LI.

2.
Front Genet ; 13: 949437, 2022.
Article in English | MEDLINE | ID: mdl-36051698

ABSTRACT

Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying ABCA4 and USH2A pathogenic biallelic mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in ABCA4 (c.4926C>G and c.5044_5058del) and USH2A (c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of USH2A-related conditions.

3.
Clin Genet ; 87(3): 259-65, 2015 Mar.
Article in English | MEDLINE | ID: mdl-24712887

ABSTRACT

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by iron accumulation in the brain, because of mutations in the PANK2 gene. Phenotypic and genotypic characteristics of 11 patients from five Mexican families with PKAN disease are reported. Sequencing of PANK2 confirmed the diagnosis. The 11 patients had dysarthria associated with dystonia and Parkinsonism in six. Brain magnetic resonance imaging (MRI) showed the 'eye-of-the-tiger' sign in all patients. Three different mutations were identified, a novel one (p.A469P) and two (p.G219V and p.N404I) very rare. Homozygous sibs for the p.G219V mutation had a severe disease progression with early death. Dystonia predominated in the p.A469P/p.N404I compound heterozygous patients. Homozygous for p.N404I showed Parkinsonism, tics and personality and speech disorders. Early and late disease onset and variable expression was present in carriers of the different identified mutations. The 'eye-of-the-tiger' is an excellent neuroimaging hallmark to predict PANK2 mutations. We detected a 'cluster' of patients harboring the p.N404I mutation, strongly suggesting a founder effect for this mutation. This is the first familial clinical-genetic PKAN disease study accomplished in Mexico.


Subject(s)
Family , Magnetic Resonance Imaging , Pantothenate Kinase-Associated Neurodegeneration/diagnosis , Pantothenate Kinase-Associated Neurodegeneration/genetics , Adolescent , Brain/pathology , Child , Child, Preschool , Female , Founder Effect , Genetic Association Studies , Genotype , Humans , Male , Mexico , Mutation , Pedigree , Phenotype , Phosphotransferases (Alcohol Group Acceptor)/genetics , Sequence Analysis, DNA
4.
Eur J Med Genet ; 56(11): 606-8, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24075960

ABSTRACT

Pantothenate kinase-associated neurodegeneration (PKAN) disease is an autosomal recessive neurodegenerative disorder with iron storage in the brain due to PANK2 gene mutations. Brain magnetic resonance imaging (MRI) shows the typical "eye-of-the-tiger" sign. The aim of the present study was to describe clinical, MRI and molecular findings in a 26-year-old male with atypical PKAN disease in whom, brain MRI scans showed bilateral pallidal T2-hypointensity with a small central region of T2-hyperintensity, resembling the "eye-of-the-tiger" typical image. Genetic analysis identified two mutations in PANK2: c.1561G>A and c.1663G>A, being the latter never described before. Due to limited phenotype-genotype correlation among patients with movement disorders, if "eye-of-the-tiger" brain MRI is present, PANK2 mutations investigation are needed to confirm PKAN disease.


Subject(s)
Mutation, Missense , Pantothenate Kinase-Associated Neurodegeneration/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Adult , Genotype , Humans , Male , Pantothenate Kinase-Associated Neurodegeneration/diagnosis , Phenotype
5.
Case Rep Genet ; 2013: 349725, 2013.
Article in English | MEDLINE | ID: mdl-23509643

ABSTRACT

Craniofrontonasal syndrome (CNFS) is an X-linked disorder caused by mutations in the EFNB1 gene in which, paradoxically, heterozygous females are more severely affected than hemizygous males. In this paper, the clinical and molecular studies of a female subject with CFNS are described. A novel de novo c.473T>C (p.M158T) mutation in exon 3 of EFNB1 was demonstrated in this patient. The M158 residue of the Ephrin-B1 protein is highly conserved between species. Our results expand the mutational spectrum exposed by CNFS.

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