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Multiple de novo gene variations in a progeroid phenotype case report: haploinsufficiency mechanisms.

ABSTRACT: We are presenting the case of a 6-year-old male patient with progeroid phenotype and severe developmental delay referred to Genetic clinic. Given the complex phenotype an extensive metabolic and genetic evaluation was performed including a whole exome sequencing analysis that showed genetic variants in TTR, RELN, MYH6, PHIP, and SYNE2 genes. Patients' mother and brother were analyzed for the genetic variants in MYH6, PHIP and RELN. Both had same variants on PHIP and RELN as our patient, with no apparent phenotypical consequences. Physical examination was remarkable for dysmorphism including plagiocephaly, low set and abnormally shaped ears, up slanted palpebral fissures, hypoplastic alae nasi, and a head circumference two standard deviations below the 3^rd percentile (microcephaly). Other characteristics include wrinkled skin, a broad forehead, sparse eyelashes in lower eyelid, short palpebral fissures, upturned nares, thick lips, right occipital plagiocephaly, overfolded helix and prominent anti-helix, protuberant chest, scaphoid abdomen, digitalized thumbs, and kyphosis due to low muscle tone. The patient presented abnormal EEG with evidence of epileptic discharges. A temporal bone CT showed plagiocephaly with flattening of the right occipital bone. Brain MRI showed callosal agenesis with bilateral colpocephaly with temporal horn dilatation, parahippocampal atrophy, lissencephaly and midbrain hypoplasia. The combination of de novo gene variants mentioned above has never been reported nor correlated as the result of haploinsufficiency mechanisms. Thus, we propose haploinsufficiency and loss of heterozygosity as etiological reasons for this patient phenotype. Further proteomic studies are needed to allocate the extense of genetic influence within the clinical manifestations.

SUBMITTER: Hernandez-Hernandez C

PROVIDER: S-EPMC8572670 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Multiple de novo gene variations in a progeroid phenotype case report: haploinsufficiency mechanisms.

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