RNA analysis and computer-aided facial phenotyping help to classify a novel TRIO splice site variant
AMERICAN JOURNAL OF MEDICAL GENETICS PART A(2024)
摘要
Pathogenic variants in TRIO, encoding the guanine nucleotide exchange factor, are associated with two distinct neurodevelopmental delay phenotypes: gain-of-function missense mutations within the spectrin repeats are causative for a severe developmental delay with macrocephaly (MIM: 618825), whereas loss-of-function missense variants in the GEF1 domain and truncating variants throughout the gene lead to a milder developmental delay and microcephaly (MIM: 617061). In three affected family members with mild intellectual disability/NDD and microcephaly, we detected a novel heterozygous TRIO variant at the last coding base of exon 31 (NM_007118.4: c.4716G>A). RNA analysis from patient-derived lymphoblastoid cells confirmed aberrant splicing resulting in the skipping of exon 31 (r.4615_4716del), leading to an inframe deletion in the first Pleckstrin homology subdomain of the GEF1 domain: p. (Thr1539_Lys1572del). To test for a distinct gestalt, facial characteristics of the family members and 41 previously published TRIO cases were systematically evaluated via GestaltMatcher. Computational analysis of the facial gestalt suggests a distinguishable facial TRIO-phenotype not outlined in the existing literature.
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关键词
GestaltMatcher,mental retardation 44,splicing,TRIO-gene,TRIO-neurodevelopmental disorder
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