Exome sequencing reveals three homozygous missense variants in SNRPA in two sisters with syndromic intellectual disability.

Splicing-related gene mutations might affect the expression of a single gene or multiple genes and cause clinically heterogeneous diseases. With the advent of next-generation sequencing, several splicing gene mutations have been exposed, yet most major spliceosome genes have no reports of germline mutations and therefore, their effects are largely unknown. We describe the previously unreported concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in 2 female siblings with 3 homozygous missense variants in SNRPA (a component of the U1 small nuclear ribonucleoprotein complex) characterized by homozygosity mapping and whole exome sequencing. Combined, c.97A>G, c.98T>C, and c.100T>A, in exon 2 of SNRPA lead to p.Ile33Ala and p.Phe34Ile exchanges, which were predicted in silico to be deleterious. Although both patients exhibited some clinical features seen in other spliceosomal disorders, their complete clinical phenotype appears to be rather uncommon, a finding that may further support the notion that mutations in components of the major spliceosome do not strictly lead to the same syndromes/phenotypes.

Mutational spectrum of the iduronate-2-sulfatase gene in Mexican patients with Hunter syndrome.

OBJECTIVE: Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which is responsible for degrading heparan and dermatan sulfate. The IDS gene is located on chromosome Xq28; pathological variants in this gene mostly consist of missense mutations and small and larger deletions, which produce different phenotypes. However, there is only one record in our population concerning the molecular mechanism of this disease; a genotype-phenotype description is not available. PATIENTS AND METHODS: There were included 24 unrelated male patients; clinical features were recorded at a database, fluorometric IDS enzyme activity testing was done for each individual, followed by Sanger sequencing to identify mutations. RESULTS: The mutational spectrum was found in 16 out of 24 Mexican patients with MPS II, and its range of phenotypes was described. The most frequent variants were of the missense type. The most affected exons were exon 3 (c.275T>G, c.284_287del, c.325T>C), exon 8 (c.1035G>C, c.550G>A), exon 9 (c.1403G>C, c.1229_1229del), and exon 7 (c.979A>C; this variant has not been previously reported). Exon 5 (c.438C>T, a non-pathogenic variant) was the least frequent. It was also found that the most severely affected patients were those with large deletions (2 out of 24) [rsaIDS: IDSP1 (P164)x0, FMR1, AFF2 (P164)x2] involving genes and pseudogenes. We found 2 patients with a synonymous mutation in exon 4. CONCLUSIONS: Our results confirmed reports in the literature, since the most frequent variants were reported in exons 3 and 8. However, this result varies from one previous report in our population, which mentions large deletions and rearrangements as the most frequent alterations, since complex rearrangements were not found. According to what has been previously found, the most severely affected patients are those in which a whole gene has been deleted.

A highly complex rea(2;3;11) and aniridia by position effect.

A two-year-old boy presenting with bilateral aniridia and psychomotor retardation had a de novo (2;3;11) highly complex rearrangement which was characterized as far as possible by means of G-banding and FISH assays with multiple probes including cosmids for the Wilms, Aniridia, Genital anomalies and Retardation (WAGR) region, alphoid repeats for chromosomes 2, 3 and 11, subtelomere probes for 2p/2q, 3p/3q and 11q and BACs for 2q32 and 3q13. We identified approximately 15 breakpoints with at least three interchromosomal and three intrachromosome anomalies involving chromosome 11. Both parents had normal karyotypes and no cryptic 11p rearrangements revealed by the chromosome 11 cosmid panel. The lack of a deletion of PAX6 pointed to the direct insertion of an approximately 300-kb segment involving the cosmids FO2121 and AO4160, and more specifically the insertion's proximal breakpoint in the approximately 150-kb segment between FO2121 and FAT5 (PAX6), as the responsible factor for the patient's aniridia via a position effect resulting in functional haploinsufficiency of the PAX6 gene. This case illustrates the importance of recognizing that de novo complex chromosomal rearrangements found in patients with diverse clinical features may contribute to the phenotype, but that multiple mechanisms and higher levels of complexity may be unmasked by high resolution molecular cytogenetic studies.

Haplotypes Eco47 III-Nsp I sites frequencies on the IDUA gene in Mexican native population.

BACKGROUND: The frequency of haplotypes of Nsp I-Eco47 III sites, at the IDUA (alpha-L iduronidase) gene, in Huichol, Tarahumara and Mestizo Mexican population is reported. METHODS: Eco47 III and Nsp I intragenic polymorphisms in IDUA gene are studied in three (Mestizo, Huichol and Tarahumara populations) Mexican groups. Data from normal Australian [Hum. Genet. 90 (1992) 327] individuals were considered for comparative analyses. RESULTS: The genotypes for IDUA Eco47 III and Nsp I sites in Mexicans were in agreement with Hardy-Weinberg equilibrium. Allele frequency distributions for individual sites differed (P < 0.05) except at site B1 in the Huichol group. Haplotype Eco47 III-Nsp I frequency distributions were different in the three Mexican normal groups, and it was also observed when to compared with the normal Australians. CONCLUSIONS: This characteristic makes the two IDUA polymorphic sites useful for identification purposes, and these polymorphisms could be included in a PCR based battery of DNA markers.

GSTT1 gene deletion is associated with lung cancer in Mexican patients.

Glutathione S-transferase (GST) is a dimeric detoxifying isoenzyme, involved in the deactivation of carcinogens, several tobacco-derived carcinogens, and xenobiotics. It catalyzes the reduction of glutathione to its thioester; thus, deficiency in GST activity due to homozygous deletion of the GSTT1 gene (null genotype) may play a role in the induction of lung cancer by smoking. We studied the distribution of GSTT1 gene deletion in peripheral blood DNA samples from 178 healthy controls (41 nonsmokers, 63 passive smokers and 74 smokers) and 52 lung cancer patients. Comparisons between groups showed that there was an increased lung cancer risk for individuals with the GSTT1 null genotype. Cancer patients showed significant differences when compared with controls: nonsmokers, passive smokers, and smokers. Twenty-one percent of lung cancer patients carried the deletion versus 2% among nonsmokers not exposed to passive smoking, 6% among passive smokers, and 5% among smokers. Thus, there is a significant association between this genotype and the possibility to risk of developing lung cancer.

Crouzon with acanthosis nigricans. Further delineation of the syndrome.

Patients with Crouzon and acanthosis nigricans syndrome show craniofacial features similar to those observed in patients with classic Crouzon syndrome, in addition to acanthosis nigricans with peculiar characteristics. More severe physical manifestations, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, which are unusual in individuals with classic Crouzon syndrome, are reported in these patients. The molecular abnormality associated with Crouzon syndrome with acanthosis nigricans (CAN) is a transition in the transmembrane domain of the FGFR3 gene that results in an Ala391Glu mutation. We describe two unrelated patients showing this mutation and compare their clinical features with those of other patients with CAN reported in the literature. In addition to craniosynostosis with crouzonoid facies and acanthosis nigricans (present in all patients), melanocytic nevi, choanal atresia or stenosis, hydrocephalus, Chiari malformations and oral abnormalities were observed in the majority of the 35 patients analyzed. Vertebral anomalies and conductive hearing loss were present with less frequency. Some characteristics considered typical of this condition (jaw cementomas, acanthomas and finger abnormalities) were absent in most of the patients.

Mucopolysaccharidosis I: a comparative study of haplotypes Eco47III-NspI sites frequencies in patients and healthy subjects of Mexican population.

BACKGROUND: Mucopolysaccharidosis I (MPS-I) is an autosomal recessive disorder, which is caused by mutations in the IDUA gene. It induces the deficiency of glycosidase alpha-L-duronidase. The enzyme that is required for the degradation of heparan and dermatan sulfate. This disorder expresses a wide range of clinical symptoms (severe mental retardation, skeletal deformations, hepatosplenomegaly, corneal clouding and mild visceral organ involvement). In the present paper, we report the frequencies of haplotypes of the Eco47III-NspI sites, in the IDUA gene, in Mexican healthy and in MPS-I individuals. METHODS: Eco47III and NspI intragenic polymorphisms in IDUA gene were studied in 262 (524 chromosomes) Mexican healthy subjects and in 53 (106 chromosomes) MPS-I patients. RESULTS: The genotypes for IDUA Eco47III and NspI sites in Mexicans were in agreement with Hardy-Weinberg expectations. Allele frequency distributions for individual sites differed (P < 0.05) in both groups. Haplotype Eco47III-NspI frequencies of Mexican MPS-I patients also differed from those of the normal Mexican population. The data provide evidence of linkage disequilibrium, since the MPS-I group constitutes a subset of the Mexican control population. The disequilibrium in Mexican MPS-I patients was defined by an increase in the haplotype A1B2, and deficiency in A2B1, with respect to normal population (P < 0.05). CONCLUSIONS: Our results support that these polymorphisms can be associated to mutations in IDUA gene, which leads to MPS-I in Mexican patients. On the other hand, these polymorphisms can be used to identify heterozygosity when they are informative.

Cytochrome P4501A1 polymorphism is associated with susceptibility to acute lymphoblastic leukemia in adult Mexican patients.

We studied the role of cytochrome P4501A1 (CYP1A1 Val/Val) genotypes in the etiology of acute lymphoblastic leukemia (ALL) in adult Mexican patients. Distributions of CYP1A1 Val/Val genotypes in peripheral blood DNA samples from 136 healthy controls and 136 adult patients with ALL were evaluated. There was an increased frequency of the CYP1A1 Val/Val genotype among ALL patients, showing a significant association between this genotype and the risk of developing ALL.