Dataset Information

Rasopathies case report: concurrence of two pathogenic variations de novo in NF1 and KRAS genes in a patient.

ABSTRACT: BACKGROUND:Rasopathies are a group of genetic malformative syndromes including neurofibromatosis 1, Noonan, LEOPARD, Costello, cardio-facio-cutaneous, Legius, and capillary malformation-arteriovenous malformation syndromes. CASE PRESENTATION:We present a female newborn that consulted at the emergency department with refusal to eat and sleepiness. A shortened femur, thickened nucal fold and suspect for agenesis of the corpus callosum were observed in prenatal ultrasound. Her phenotype included hypertelorism, antimongoloid obliquity of the palpebral fissure, prominent forehead, long filtrum, thickened nucal fold, separated nipples, widespread thickened skinfolds and café-au-lait spots. She had a systolic murmur due to pulmonary valve stenosis. The NF1 gene testing found the pathogenic variant p.E2586X (c.7756G?>?T) in exon 53, not described in any international database or scientific publications yet. Also, a mutation in the Kras gene was detected (p.Val14lle), which is associated with mild Noonan phenotype. Both variations were de novo. CONCLUSIONS:Not all genes and mutations have already been discovered, so it's important to document new findings, like our patient's, to enrich and update the international database and broaden all possible knowledge about rasopathies. This is the first case to be described presenting simultaneously two mutations in Kras and NF1 genes, whose possible synergic effect regarding its pathogenicity is unknown, but could be interesting towards therapeutic alternatives.

SUBMITTER: Baquedano Lobera I

PROVIDER: S-EPMC6449997 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Rasopathies case report: concurrence of two pathogenic variations de novo in NF1 and KRAS genes in a patient.

Baquedano Lobera Irene I Izquierdo Álvarez Silvia S Oliván Del Cacho María Jesús MJ

BMC pediatrics 20190405 1

<h4>Background</h4>Rasopathies are a group of genetic malformative syndromes including neurofibromatosis 1, Noonan, LEOPARD, Costello, cardio-facio-cutaneous, Legius, and capillary malformation-arteriovenous malformation syndromes.<h4>Case presentation</h4>We present a female newborn that consulted at the emergency department with refusal to eat and sleepiness. A shortened femur, thickened nucal fold and suspect for agenesis of the corpus callosum were observed in prenatal ultrasound. Her phenot ...[more]

PMID: 30953504

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Project description:BACKGROUND: Fabry disease is an X-linked inherited metabolic condition where the deficit of the ?-galactosidase A enzyme, encoded by the GLA gene, leads to glycosphingolipid storage, mainly globotriaosylceramide. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD, including missense and nonsense mutations, small and large deletions. Such mutations are usually inherited, and cases of de novo onset occur rarely. CASE PRESENTATION: In this article we report an interesting case of a 44-year-old male patient suffering from a severe form of Fabry disease, with negative family history. The patient showed signs such as cornea verticillata, angiokeratomas, cardiac and neurological manifestations, an end-stage renal disease and he had low ?-galactosidase A activity. We detected, in this subject, the mutation c.493 G > C in the third exon of the GLA gene which causes the amino acid substitution D165H in the protein. This mutation affects the amino acid - belonging to the group of buried residues - involved, probably, in the preservation of the protein folding. Moreover, studies of multiple sequence alignment indicate that this amino acid is highly conserved, thus strengthening the hypothesis that it is a key amino acid to the enzyme functionality.The study of the relatives of the patient showed that, surprisingly, none of the members of his family of origin had this genetic alteration, suggesting a de novo mutation. Only his 11-year-old daughter - showing acroparaesthesias and heat intolerance with reduced enzymatic activity - had the same mutation. CONCLUSIONS: We suggest that a non-inherited mutation of the ?-galactosidase A gene is responsible for Fabry disease in the patient who had reduced enzyme activity and classical clinical manifestations of the disease. In a family, it is rare to find only one Fabry disease affected subject with a de novo mutation. These findings emphasize the importance of early diagnosis, genetic counselling, studying the genealogical tree of the patients and starting enzyme replacement therapy to prevent irreversible vital organ damage that occurs during the course of the disease.

Project description:Long interspersed (L1) and Alu elements are actively amplified in the human genome through retrotransposition of their RNA intermediates by the -100 still retrotranspositionally fully competent L1 elements. Retrotransposition can cause inherited disease if such an element is inserted near or within a functional gene. Using direct cDNA sequencing as the primary assay for comprehensive NF1 mutation analysis, we uncovered in 18 unrelated index patients splicing alterations not readily explained at the genomic level by an underlying point-mutation or deletion. Improved PCR protocols avoiding allelic drop-out of the mutant alleles uncovered insertions of fourteen Alu elements, three L1 elements, and one poly(T) stretch to cause these splicing defects. Taken together, the 18 pathogenic L1 endonuclease-mediated de novo insertions represent the largest number of this type of mutations characterized in a single human gene. Our findings show that retrotransposon insertions account for as many as -0.4% of all NF1 mutations. Since altered splicing was the main effect of the inserted elements, the current finding was facilitated by the use of RNA-based mutation analysis protocols, resulting in improved detection compared to gDNA-based approaches. Six different insertions clustered in a relatively small 1.5-kb region (NF1 exons 21(16)-23(18)) within the 280-kb NF1 gene. Furthermore, three different specific integration sites, one of them located in this cluster region, were each used twice, i.e. NM_000267.3(NF1):c.1642-1_1642 in intron 14(10c), NM_000267.3(NF1):c.2835_2836 in exon 21(16), and NM_000267.3(NF1):c.4319_4320 in exon 33(25). Identification of three loci that each served twice as integration site for independent retrotransposition events as well as 1.5-kb cluster region harboring six independent insertions supports the notion of non-random insertion of retrotransposons in the human genome. Currently, little is known about which features make sites particularly vulnerable to L1 EN-mediated insertions. The here identified integration sites may serve to elucidate these features in future studies.

Dataset Information

Rasopathies case report: concurrence of two pathogenic variations de novo in NF1 and KRAS genes in a patient.

Publications

Rasopathies case report: concurrence of two pathogenic variations de novo in NF1 and KRAS genes in a patient.

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