Germline and mosaic mutations of FLN1 in men with periventricular heterotopia
R Guerrini1, D Mei, S Sisodiya
1Division of Child Neurology and Psychiatry, University of Pisa and IRCCS Fondazione Stella Maris, via dei Giacinti 2, 56018 Calambrone Pisa, Italy. renzo.guerrini@inpe.unipi.it
Objective:
To describe the phenotypic spectrum and genetics of periventricular nodular heterotopia (PNH) caused by FLN1 mutations in four men.
Background:
X-linked PNH caused by FLN1 mutations (MIM #300049) implies prenatal or early postnatal lethality in boys and 50% recurrence risk in daughters of affected women.
Methods:
Clinical examination, cognitive testing, MRI, and mutation analysis (denaturing high-performance liquid chromatography and direct sequencing) on blood lymphocytes and single hair roots were performed for nine affected individuals, including three men. Neuropathologic study of the brain was performed for an affected boy.
Results:
In two families, missense mutations were transmitted from mother to son (Met102Val) and from father to daughter (Ser149Phe), causing mild phenotypes in both genders, including unilateral PNH. In a third family, a man was mosaic for an A>G substitution (intron 11 acceptor splice site) on leukocyte DNA and hair roots (mutant = 42% and 69%). Single hair root analysis confirmed that the mutation was not present in all ectodermal derivative cells. A healthy daughter had inherited the X chromosome from her father's wild-type germinal cell population. In the fourth family, an eight-base deletion (AGGAGGTG, intron 25 donor splice site) led to early deaths of boys. Postmortem study in a newborn boy revealed PNH and cardiovascular, genitourinary, and gut malformations.
Conclusions:
Periventricular nodular heterotopia caused by FLN1 mutations in men has a wide clinical spectrum and is caused by different genetic mechanisms, including somatic mosaicism. Mutation analysis of FLN1 should support genetic counseling in men with periventricular nodular heterotopia.
Insights
FLN1 mutations cause periventricular nodular heterotopia (PNH) in males, with varied clinical presentations and genetic causes, including mosaicism. FLN1 mutation analysis aids genetic counseling for men with PNH.
Area of Science:
- Neurogenetics
- Developmental neuroscience
- Clinical genetics
Background:
- Periventricular nodular heterotopia (PNH) is a neuronal migration disorder.
- X-linked PNH due to FLN1 mutations typically results in severe outcomes for males.
- Understanding genetic mechanisms is crucial for diagnosis and counseling.
Observation:
- Phenotypic variability in males with FLN1 mutations ranges from mild unilateral PNH to severe malformations and early lethality.
- Somatic mosaicism for FLN1 mutations can occur, influencing inheritance patterns and clinical presentation.
- Genetic analysis revealed missense mutations and splice site mutations in affected families.
Findings:
- Identified missense mutations (Met102Val, Ser149Phe) causing mild PNH in both genders.
- Documented somatic mosaicism in a male with an intron 11 splice site mutation.
- Observed an eight-base deletion in intron 25 leading to severe malformations and lethality in males.
Implications:
- FLN1 mutation analysis is essential for accurate diagnosis and genetic counseling in males with PNH.
- Recognizing the wide spectrum of PNH phenotypes and genetic mechanisms is critical for patient management.
- This study highlights the complex genetic underpinnings of X-linked PNH.
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