A novel heterozygous KRIT1 initiation-region duplication (NM_004912.4: c.2dup) causing predicted loss of all major functional domains was identified in a pediatric family with familial cerebral cavernous malformation, illustrating wide intrafamilial clinical variability ranging from asymptomatic radiological disease to epilepsy and fatal hemorrhage.
Key Findings
Results
A previously unreported heterozygous KRIT1 initiation-region frameshift variant was identified in a pediatric family with familial cerebral cavernous malformation.
The variant is a duplication at position NM_004912.4: c.2dup, predicted to result in p.(Met1IlefsTer31).
The variant is predicted to cause loss of all major functional domains of the KRIT1 protein.
The variant was identified via whole-exome sequencing and confirmed by segregation analysis.
This variant had not been previously reported, expanding the known KRIT1 mutational spectrum.
Results
The index patient was a 14-year-old boy presenting with focal seizure and a progressively enlarging right parietal calvarial mass.
Brain and spinal MRI revealed multiple cerebral and cerebellar cerebral cavernous malformations (CCMs) along with a cervical intramedullary cavernous malformation.
The calvarial lesion was surgically excised and confirmed histopathologically as a hemangioma.
Clinical, radiological, histopathological, and molecular findings were all reviewed as part of the workup.
Results
The same KRIT1 variant was detected in the index patient's clinically asymptomatic sibling, who had MRI-confirmed multiple CCMs.
The sibling harbored the identical heterozygous KRIT1 c.2dup variant.
Despite MRI-confirmed multiple CCMs, the sibling remained clinically asymptomatic, demonstrating intrafamilial phenotypic variability.
Segregation analysis was used to confirm variant presence in the sibling.
Results
The mother tested negative for the KRIT1 variant, while the father, who had died from intracerebral hemorrhage, was unavailable for genetic testing.
The mother did not carry the c.2dup KRIT1 variant.
The father had died from intracerebral hemorrhage, suggesting a severe clinical manifestation consistent with CCM.
Genetic testing of the father was unavailable due to his death prior to evaluation.
The family demonstrated a clinical spectrum from asymptomatic radiological disease to epilepsy and fatal hemorrhage within a single kindred.
Background
Familial cerebral cavernous malformation caused by KRIT1 loss-of-function variants is an autosomal dominant vascular disorder with age-dependent penetrance and marked intrafamilial variability.
KRIT1 loss-of-function variants are described as the most common genetic cause of familial CCM.
The condition is characterized by autosomal dominant inheritance with age-dependent penetrance.
Pediatric genotype-phenotype correlations for this condition are noted to remain limited in the existing literature.
Conclusions
The authors conclude that findings support early molecular diagnosis, cascade screening, and susceptibility-sensitive MRI surveillance in families with KRIT1-related CCM.
The wide intrafamilial clinical range—from asymptomatic radiological disease to epilepsy and fatal hemorrhage—underscores the importance of proactive family screening.
Cascade screening was recommended given the autosomal dominant inheritance pattern.
Susceptibility-sensitive MRI was specifically recommended for surveillance given the radiological nature of some presentations.
What This Means
This research describes a family in which a new genetic mutation was discovered that causes a brain blood vessel condition called familial cerebral cavernous malformation (CCM). CCMs are clusters of abnormal blood vessels in the brain and spinal cord that can bleed and cause serious problems. The mutation was found in the KRIT1 gene and had never been reported before. It was identified in a 14-year-old boy who had seizures, multiple CCMs in his brain and spinal cord, and an unusual bony growth on his skull, as well as in his sibling who had no symptoms at all despite having multiple CCMs visible on MRI scans. The children's mother did not carry the mutation, and their father—who was unavailable for testing—had died from a brain hemorrhage, which is a known severe complication of CCM.
This case is notable because it shows just how differently the same genetic mutation can affect people in the same family. One sibling had seizures and a skull lesion, another had no symptoms at all, and a parent died from a brain bleed—all potentially linked to the same inherited gene change. This wide range of outcomes within a single family highlights why CCM can be difficult to predict and manage.
This research suggests that when a child or adult is diagnosed with CCM and a KRIT1 mutation is found, other family members should be offered genetic testing even if they have no symptoms, because they may still have brain lesions that need monitoring. Early genetic diagnosis and regular MRI brain scans using imaging techniques sensitive to blood vessel abnormalities could help identify at-risk individuals before serious complications such as hemorrhage occur.