RNA analysis and computer-aided facial phenotyping help to classify a novel TRIO splice site variant.
Am J Med Genet A
; 194(7): e63599, 2024 07.
Article
en En
| MEDLINE
| ID: mdl-38517182
ABSTRACT
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_007118.4c.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 in-frame 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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Linaje
/
Fenotipo
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Factores de Intercambio de Guanina Nucleótido
/
Sitios de Empalme de ARN
Límite:
Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Med Genet A
Asunto de la revista:
GENETICA MEDICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Alemania