Deletion in COL4A2 is associated with a three-generation variable phenotype: from fetal to adult manifestations.
Eur J Hum Genet
; 29(11): 1654-1662, 2021 11.
Article
en En
| MEDLINE
| ID: mdl-33837277
ABSTRACT
Genetic alterations in COL4A2 are less common than those of COL4A1 and their fetal phenotype has not been described to date. We describe a three-generation family with an intragenic deletion in COL4A2 associated with a prenatal diagnosis of recurrent fetal intracerebral hemorrhage (ICH), and a myriad of cerebrovascular manifestations. Exome sequencing, co-segregation analysis, and imaging studies were conducted on eight family members including two fetuses with antenatal ICH. Histopathological evaluation was performed on the terminated fetuses. An intragenic heterozygous pathogenic in-frame deletion; COL4A2, c.4151_4168del, (p.Thr1384_Gly1389del) was identified in both fetuses, their father with hemiplegic cerebral palsy (CP), as well as other family members. Postmortem histopathological examination identified microscopic foci of heterotopias and polymicrogyria. The variant segregated in affected individuals demonstrating varying degrees of penetrance and a wide phenotypic spectrum including periventricular venous hemorrhagic infarction causing hemiplegic CP, polymicrogyria, leukoencephalopathy, and lacunar stroke. We present radiographic, pathological, and genetic evidence of prenatal ICH and show, for what we believe to be the first time, a human pathological proof of polymicrogyria and heterotopias in association with a COL4A2 disease-causing variant, while illustrating the variable phenotype and partial penetrance of this disease. We highlight the importance of genetic analysis in fetal ICH and hemiplegic CP.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Hemorragia Cerebral
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Eliminación de Gen
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Penetrancia
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Colágeno Tipo IV
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Adult
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Eur J Hum Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Israel