Multiple Cerebral Cavernous Malformations Research Articles

Loss of heterozygosity in CCM2 cDNA revealing a structural variant causing multiple cerebral cavernous malformations.

Loss-of-function variants in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations. However, genomic DNA sequencing combined with large rearrangement screening fails to detect a pathogenic variant in 5% of the patients. We report a family with two affected members harboring multiple CCM lesions, one with severe hemorrhages and one asymptomatic. No causative variant was detected using DNA sequencing of the three CCM genes, CNV detection analysis, and RNA sequencing. However, a loss of heterozygosity in CCM2 was observed on cDNA sequences in one of the two affected members, which strongly suggested that this locus might be involved. Whole genome sequencing (WGS) identified a balanced structural variant on chromosome 7 with a breakpoint interrupting the CCM2 gene, preventing normal mRNA synthesis. These data underline the importance of WGS in undiagnosed patients with typical multiple CCM.

397 Rehemorrhage of Brainstem Cavernous Malformations: A Benchmark Approach to Individualized Risk and Severity Assessment

INTRODUCTION: Brainstem cavernous malformations (BSCMs) represent a unique subgroup of cavernous malformations with more hemorrhagic presentation and technical challenges. METHODS: A total of 123 consecutive BSCM patients with symptomatic hemorrhage were identified between 2015 and 2022, with untreated follow-up > 12 months or subsequent hemorrhage during the untreated follow-up. Nomograms were proposed to individualize the assessment of subsequent hemorrhage risk and neurological status (determined by the modified Rankin Scale [mRS] score) after future hemorrhage. The least absolute shrinkage and selector operation (LASSO) regression was used for feature screening. The calibration curve and concordance index (C-index) were used to assess the internal calibration and discrimination performance of the nomograms. Cross-validation was further performed to validate the accuracy of the nomograms. RESULTS: Prior hemorrhage times (adjusted OR [aOR] 6.78 per ictus increase) and Zabramski type I or V (OR 11.04) were associated with rehemorrhage within 1 year. A lower mRS score after previous hemorrhage (aOR 0.38 for a shift to a higher mRS score), Zabramski type I or V (OR 3.41), medulla or midbrain location (aOR 2.77), and multiple cerebral cavernous malformations (aOR 11.76) were associated with worsened neurological status at subsequent hemorrhage. The nomograms showed good accuracy and discrimination, with a C-index of 0.80 for predicting subsequent hemorrhage within 1 year and 0.71 for predicting neurological status after subsequent hemorrhage, which were maintained in cross-validation. CONCLUSIONS: An individualized approach to risk and severity assessment of BSCM rehemorrhage was feasible with clinical and imaging features.

Rehemorrhage of brainstem cavernous malformations: a benchmark approach to individualized risk and severity assessment.

Brainstem cavernous malformations (BSCMs) represent a unique subgroup of cavernous malformations with more hemorrhagic presentation and technical challenges. This study aimed to provide individualized assessment of the rehemorrhage clustering risk of BSCMs after the first symptomatic hemorrhage and to identify patients at higher risk of neurological deterioration after new hemorrhage, which would help in clinical decision-making. A total of 123 consecutive BSCM patients with symptomatic hemorrhage were identified between 2015 and 2022, with untreated follow-up > 12 months or subsequent hemorrhage during the untreated follow-up. Nomograms were proposed to individualize the assessment of subsequent hemorrhage risk and neurological status (determined by the modified Rankin Scale [mRS] score) after future hemorrhage. The least absolute shrinkage and selector operation (LASSO) regression was used for feature screening. The calibration curve and concordance index (C-index) were used to assess the internal calibration and discrimination performance of the nomograms. Cross-validation was further performed to validate the accuracy of the nomograms. Prior hemorrhage times (adjusted OR [aOR] 6.78 per ictus increase) and Zabramski type I or V (OR 11.04) were associated with rehemorrhage within 1 year. A lower mRS score after previous hemorrhage (aOR 0.38 for a shift to a higher mRS score), Zabramski type I or V (OR 3.41), medulla or midbrain location (aOR 2.77), and multiple cerebral cavernous malformations (aOR 11.76) were associated with worsened neurological status at subsequent hemorrhage. The nomograms showed good accuracy and discrimination, with a C-index of 0.80 for predicting subsequent hemorrhage within 1 year and 0.71 for predicting neurological status after subsequent hemorrhage, which were maintained in cross-validation. An individualized approach to risk and severity assessment of BSCM rehemorrhage was feasible with clinical and imaging features.

Fahr disease presenting with multiple cerebral calcifications

Fahr disease, also known as idiopathic basal ganglion calcification, is a rare and genetically heterogeneous neurological disorder. Herein, we report a rare case of Fahr disease presenting with multiple cerebral calcifications. A 63-year-old woman presented with dizziness to a local clinic. Brain computed tomography performed on admission revealed multiple high-intensity lesions in both basal ganglia, both cerebellar hemispheres, and the left frontal lobe. In contrast, brain magnetic resonance imaging (MRI) showed no prominent lesions on T2- and T1-weighted images, and there was no contrast enhancement after gadolinium injection. However, multiple dark signals were detected on gradient echo MRI. The location and radiological appearance of the lesion resembled those of a physiological intracranial calcification, except for asymmetric calcification in both cerebellar hemispheres and the left frontal subcortical white matter. The patient was diagnosed with basal ganglion calcification with multiple cerebral cavernous malformations or, less likely, brain tumors. Through a careful radiological and clinical review, the calcifications were diagnosed as Fahr disease. Follow-up was planned. It is important to consider the presence of multiple intracranial calcifications in the basal ganglia, cerebellum, or deep subcortical white matter as a warning sign for Fahr disease.

A novel KRIT1/CCM1 mutation accompanied by a NOTCH3 mutation in a Chinese family with multiple cerebral cavernous malformations.

Family cerebral cavernous malformations (FCCMs) are mainly inherited through the mutation of classical CCM genes, including CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. FCCMs can cause severe clinical symptoms, including epileptic seizures, intracranial hemorrhage (ICH), or functional neurological deficits (FNDs). In this study, we reported a novel mutation in KRIT1 accompanied by a NOTCH3 mutation in a Chinese family. This family consists of 8 members, 4 of whom had been diagnosed with CCMs using cerebral MRI (T1WI, T2WI, SWI). The proband (II-2) and her daughter (III-4) had intracerebral hemorrhage and refractory epilepsy, respectively. Based on whole-exome sequencing (WES) data and bioinformatics analysis from 4 patients with multiple CCMs and 2 normal first-degree relatives, a novel KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in intron 13 was considered a pathogenic gene in this family. Furthermore, based on 2 severe and 2 mild CCM patients, we found an SNV missense mutation, NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C), in NOTCH3. Finally, the KRIT1 and NOTCH3 mutations were validated in 8 members using Sanger sequencing. This study revealed a novel KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in a Chinese CCM family, which had not been reported previously. Moreover, the NOTCH3 mutation NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C) might be a second hit and associated with the progression of CCM lesions and severe clinical symptoms.

A Rare Co-Existence of Multiple Cerebral Cavernous Malformations and Pleomorphic Adenoma of the Parotid Gland in Myotonic Dystrophy.

Myotonic dystrophy is an autosomal dominant inherited disorder primarily affecting muscle function. Myotonia, progressive muscle weakness and wasting, and associated systemic involvement, i.e., cataracts, cardiac conduction defects and endocrine abnormalities especially insulin resistance, are the characteristic features. Recent evidence has shown an increased risk of developing benign as well as malignant tumours in such patients. We report a 39-year male of myotonic dystrophy who presented with multiple cerebral cavernous malformations in addition to pleomorphic adenoma of the parotid gland. Though the association of myotonic dystrophy with salivary gland neoplasms has been sparsely documented in the literature, but the co-existence with multiple cerebral cavernous malformations has not been reported so far. Our case is the first of its kind. Key Words: Cerebral cavernous malformations, Myotonic dystrophy, Parotid gland, Pleomorphic adenoma.

A Rare Co-Existence of Multiple Cerebral Cavernous Malformations and Pleomorphic Adenoma of the Parotid Gland in Myotonic Dystrophy

A Rare Co-Existence of Multiple Cerebral Cavernous Malformations and Pleomorphic Adenoma of the Parotid Gland in Myotonic Dystrophy

INNV-05. CO-OCCURRENCES OF A HIGH-GRADE GLIOMA WITH CAVERNOUS MALFORMATIONS AND PATHOGENIC VARIANTS IN PDCD10 AND SMARCA4

Abstract INTRODUCTION The co-occurrence of multiple disease processes can make for more challenging diagnoses. Here we report an unusual case of a patient found to have an IDH1-mutant high-grade glioma along with multiple cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. Case Description: A 17-year-old female presented with left arm paresthesia and weakness along with persistent headaches within the frontal and occipital regions that progressed in intensity to include nausea and emesis. A fast sequence magnetic resonance imaging (MRI) of her head was obtained that revealed the presence of multiple bilateral cystic lesions suspicious for cavernomas with the most notable lesion in the right parietal lobe. Ophthalmology consultation revealed grade III papilledema bilaterally. A full brain MRI with and without contrast was obtained and demonstrated a right anterior parietal lobe lesion with associated mass effect, as well as multiple bilateral supratentorial and left cerebellar cavernous malformations. The patient underwent tumor debulking of her dominant lesion. Pathology revealed an IDH1 mutant diffuse astrocytoma, WHO grade 3. Germline genetic testing was pursued which revealed a PDCD10 pathogenic variant consistent with familial cerebral cavernous malformation syndrome and a likely pathogenic variant in SMARCA4. Treatment of her high-grade-glioma included radiation therapy followed by maintenance oral temozolomide. DISCUSSION This case illustrates the unusual co-occurrences of a high-grade glioma with familial cavernous malformation syndrome and germline pathogenic variants in PDCD10 and SMARCA4. Our patient continues to do well clinically, but because of her now significant risk of developing ovarian cancer she has elected to undergo a prophylactic bilateral salpingo-oophorectomy. Recognition of abnormal genetic results is critical in the setting of multiple disease processes and can play a crucial role in the on-going care for a patient.

Clinical characteristics and long-term outcome of cerebral cavernous malformations-related epilepsy.

Cerebral cavernous malformations (CCMs) present variably, and epileptic seizures are the most common symptom. The factors contributing to cavernoma-related epilepsy (CRE) and drug resistance remain inconclusive. The outcomes of CRE after different treatment modalities have not yet been fully addressed. This study aimed to characterize the clinical features of patients with CRE and the long-term seizure outcomes of medical and surgical treatment strategies. This was a retrospective cohort of 135 patients with CCM who were diagnosed in 2007-2011 and followed up for 93.6months on average. The patients were divided into drug-resistant epilepsy (DRE; n= 29), non-DRE (n= 45), and no epilepsy (NE; n= 61). Temporal CCM was the factor most strongly associated with the development of both CRE and DRE. The majority of patients with single temporal CCMs had CRE (86.8%, n= 33), and 50% had DRE, whereas only 14.7% (n= 5) with a nontemporal supratentorial CCM had DRE (p< .05). The most common lesion site in the DRE group was the mesiotemporal lobe (50%). Multiple CCMs were more frequently observed in the CRE (29.2%) than the NE (11.5%) group (p< .05). In patients with CRE, multiple lesions were associated with a higher rebleeding rate (odds ratio=11.1), particularly in those with DRE (odds ratio=15.4). The majority of patients who underwent resective surgery for DRE (76.5%, n= 13) achieved International League Against Epilepsy Class I and II seizure outcomes even after a long disease course. Temporal CCM not only predisposes to CRE but also is a major risk factor for drug resistance. The mesiotemporal lobe is the most epileptogenic zone. Multiple CCMs are another risk factor for CRE and increase the rebleeding risk in these patients. Surgical resection could provide beneficial long-term seizure outcomes in patients with DRE.

HGG-19. Co-occurrences of a high-grade glioma with cavernous malformations and pathogenic variants inPDCD10 andSMARCA4

INTRODUCTION: The co-occurrence of multiple disease processes can make for more challenging diagnoses. Here we report an unusual case of a patient found to have an IDH1-mutant high-grade glioma along with multiple cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. CASE DESCRIPTION: A 17-year-old female presented with left arm paresthesia and weakness along with persistent headaches within the frontal and occipital regions that progressed in intensity to include nausea and emesis. A fast sequence magnetic resonance imaging (MRI) of her head was obtained that revealed the presence of multiple bilateral cystic lesions suspicious for cavernomas, with the most notable lesion in the right parietal lobe. Ophthalmology consultation revealed grade III papilledema bilaterally. A full brain MRI with and without contrast was obtained and demonstrated a right anterior parietal lobe lesion with associated mass effect, as well as multiple bilateral supratentorial and left cerebellar cavernous malformations. The patient underwent tumor debulking of her dominant lesion. Pathology revealed an IDH1-mutant diffuse astrocytoma, WHO grade III. Tumor genetic testing was done and identified a SMARCA4 and two TP53 variants. Germline genetic testing was then pursued which revealed a PDCD10 pathogenic variant consistent with familial cerebral cavernous malformation syndrome and a likely pathogenic variant in SMARCA4. Treatment of her high-grade-glioma included radiation therapy followed by maintenance oral temozolomide. DISCUSSION: This case illustrates the unusual co-occurrences of a high-grade glioma with familial cavernous malformation syndrome and germline pathogenic variants in PDCD10 and SMARCA4. Our patient continues to do well clinically, but because of her risk of developing small cell carcinoma of the ovary she has elected to undergo a prophylactic bilateral salpingo-oophorectomy. Recognition of abnormal genetic results is critical in the setting of multiple disease processes and can play a crucial role in the on-going care for a patient.

Magnetic Resonance Imaging of Multiple Cerebral and Spinal Cavernous Malformations of a Patient with Dementia and Tetraparesis

Cavernomas are rare cerebrovascular malformations that usually occur in sporadic forms with solitary lesions located most often in the hemispheric white matter, but also in the infratentorial or spinal region. Multiple lesions at different CNS levels are considered a hallmark for the familial form of the disease. The diagnostic modality of choice for cerebral cavernous malformations (CCMs) is magnetic resonance imaging (MRI). We present an intriguing case of a 65-year-old male admitted to our hospital with tetraparesis and cognitive impairment where highly sensitive MRI sequences identified many cerebral cavernous lesions at the supra-, infratentorial and cervical–thoracic spine levels, some of them with recent signs of bleeding in a patient with oral anticoagulant therapy due to atrial fibrillation. The mechanism of cognitive impairment in this patient is most probably the interruption of strategic white matter tracts, as it is known to happen in other subcortical vascular pathologies. MRI can be helpful not only in mapping the anatomical distribution of lesions, but also in weighing the risks and making decisions regarding whether or not to continue oral anticoagulant therapy.

Multiple cerebral cavernous malformations: Clinical course of confirmed, assumed and non-familial disease.

Analyze and compare the natural course of confirmed familial cerebral cavernous malformation (FCCM), assumed FCCM and non-familial multiple cerebral cavernous malformation (CCM) disease over a 5-year period. Our institutional database was screened for patients with CCM admitted between 2003 and 2020. Patients with complete magnetic resonance imaging dataset, evidence of multiple CCM, clinical baseline characteristics, and follow-up examination were included. Patients were separated into confirmed familial cases, assumed familial cases or non-familial multiple cavernous malformations. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for hemorrhage and recurrent hemorrhage. A total of 238 patients with multiple CCM were analyzed; 90 individuals had a confirmed FCCM disease, 115 an assumed FCCM, and 33 were allocated to the non-FCCM group. Univariate Cox regression analysis identified intracerebral hemorrhage (ICH) as mode of presentation (p=0.001) as a predictor for occurrence of recurrent hemorrhage during the 5-year follow-up (FU). The cumulative 5-year risk of (re)bleeding was 21.6% for the entire cohort, 30.7% for patients with ICH at diagnosis, 22.1% for those patients with a confirmed diagnosis of FCCM, 23.5% for those with an assumed FCCM, and 21% for the non-FCCM cases. FCCM patients with ICH at diagnosis are prone to develop rebleeding. During untreated 5-year FU, FCCM patients and patients with sporadic multiple CCM reveal an almost equal susceptibility for (re)hemorrhage. Moreover, confirmed, assumed and non-FCCM patients showed an equal cumulative 5-year risk of symptomatic ICH. The probability of hemorrhage tends to increase over time, particularly in cases with ICH at presentation.

Multiple cerebral cavernous malformations – clinical course of confirmed, assumed and non-familial disease

Multiple cerebral cavernous malformations – clinical course of confirmed, assumed and non-familial disease

Tuberous sclerosis with negative genetic testing and multiple cerebral cavernomas: A new association (Case report)

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with multisystemic involvement usually resulting from mutations in the tuberous sclerosis 1 (TSC1) or TSC2 genes. However, 10 to 25% of patients do not exhibit these mutations. Cerebral cavernous malformations (CCMs) are capillary-venous malformations that can be asymptomatic or cause variable neurological manifestations, including seizures. Familial CCMs are recognized. In both conditions, specific dermatological lesions are associated. We present the case of a 31-year-old female with TSC diagnosed at the age of 18 years who presented with negative genetic testing. She was admitted to our department in 2019 for a sudden increased frequency of focal seizures. Patient examination revealed multiple facial and intraoral angiofibroma, diplopia, right hemihypoesthesia, brisk deep tendon reflexes, and distal leg paresthesia. VideoEEG indicated a frontal paramedian epileptogenic focus. Cerebral magnetic resonance imaging (MRI) and angioMRI identified multiple fronto-parietal cortical tubers, as well as multiple CCMs, with evidence of bleeding in one. Under antiepileptic drug (AED) and mTOR inhibitor treatment, the seizure frequency significantly improved in a short period of time. This is the first reported case of tuberous sclerosis with negative genetic testing associated with multiple cerebral cavernoma. Such complex patients require multidisciplinary management and detailed genetic testing for increasing knowledge on neuro-cutaneous disorders.

Clinical, neuroradiological and genetic findings in a cohort of patients with multiple Cerebral Cavernous Malformations.

Cerebral cavernous malformations (CCM) consist of clusters of irregular dilated capillaries and represent the second most common type of vascular malformation affecting the central nervous system. CCM might be asymptomatic or cause cerebral hemorrhage, seizures, recurrent headaches and focal neurologic deficits. Causative mutations underlining CCM have been reported in three genes: KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3. Therapeutic avenues are limited to surgery. Here we present clinical, neuroradiological and molecular findings in a cohort of familial and sporadic CCM patients. Thirty subjects underwent full clinical and radiological assessment. Molecular analysis was performed by direct sequencing and MLPA analysis. Twenty-eight of 30 subjects (93%) experienced one or more typical CCM disturbances with cerebral/spinal hemorrhage being the most common (43%) presenting symptom. A molecular diagnosis was achieved in 87% of cases, with three novel mutations identified. KRIT1/CCM1 patients displayed higher risk of de novo CCMs appearance and bleedings. Magnetic Resonance Imaging (MRI) showed that infratentorial region was more frequently affected in mutated subjects while brainstem was often spared in patients with negative genetic testing.

Asymptomatic Familial Multiple Cerebral Cavernous Malformation in a 73-Year-Old Woman

Cerebral cavernous malformations (CCMs) are dilated blood vessels which can develop sporadically or in familial form and are the commonest malformations of blood vessels in the spinal cord and brain. The familial form is an autosomal dominant gene mutation disorder. This condition can be diagnosed with magnetic resonance imaging (MRI) and computed tomography (CT) scan, but the modality of choice is MRI because of its high sensitivity. We report a case of a 73-year-old woman with an asymptomatic multiple familial cerebral cavernous malformation (FCCM) which was previously misdiagnosed as multiple cerebral metastases on CT scan. A brain MRI performed correctly diagnosed her condition as FCCM based on the typical MRI appearances. In order not to misdiagnose brain lesions like CCM on CT scan, for cerebral metastases in resource-poor settings, radiologists must recommend advanced imaging modalities like MRI for further evaluation, thereby avoiding unnecessary invasive surgical biopsies.

KRIT1 Gene in Patients with Cerebral Cavernous Malformations: Clinical Features and Molecular Characterization of Novel Variants

Cerebral cavernous malformations (CCMs) are vascular malformations that may result in headaches, seizures, focal neurological deficits, and hemorrhage. CCMs occur sporadically (80%) or in familial form (20%), with autosomal dominant inheritance. Among the three CCM-related genes, mutations in KRIT1 account for 53–65% of familial cases and more than 100 different mutations have been identified so far. In the present work, we describe the clinical, neuroradiological, and genetic findings of sixteen CCM Italian patients, 13 belonging to 4 unrelated families and 3 sporadic cases. Six distinct KRIT1 gene variants, two novel (c.1730+1_1730+3del, c.1664 C>T) and four previously described (c.966G>A, c.1255-1G>A c.1197_1200del, c.1255-1_1256del), were identified, including a possible de novo mutation. All the variants resulted in a premature stop codon. Cerebral 1.5 T magnetic resonance imaging showed multiple CCMs in all the mutation carriers for whom it was available, including sporadic cases. One patient had also cutaneous angiomas. Among the mutation carriers, symptomatic patients constituted 66% and a variable phenotypic expression was observed. Our data confirms phenotypic variability and incomplete penetrance of neurological symptoms in KRIT1-positive families, expands the mutational spectrum of this gene, and highlights how sporadic cases with multiple lesions need an approach similar to individuals with familial CCM.

Multiple cerebral cavernous malformation with de novo formation after surgical treatment: a case report

Multiple cerebral cavernous malformation with de novo formation after surgical treatment: a case report

Identification of a Novel CCM1 Frameshift Mutation in a Chinese Han Family With Multiple Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCMs) are vascular lesions that predominantly occur in the brain. CCMs can be sporadic or hereditary in an autosomal dominant manner. The genes harboring variants of familial CCMs (FCCMs) include CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. In this study, we identified a novel CCM1/KRIT1 mutation in a Chinese family with FCCMs. This family consists of 20 members, and 6 of them had been diagnosed with CCMs. The proband patient is a 17-year-old female who has suffered from CCM-related intracranial hemorrhage four times. Magnetic resonance imaging (MRI) revealed four lesions in the different brain regions and one lesion has progressively enlarged. The pathological histology confirmed CCMs. Whole exome sequencing revealed a novel deletion mutation (c.1635delA) within exon 15 of CCM1/KRIT1 gene in the proband patient, her mother, and her uncle who had CCMs. This frameshift mutation led to a premature termination codon (PTC) at nucleotides 1652–1654. We also detected that the CCM1 mRNA levels in the blood lymphocytes of the family members with CCMs were reduced by 46.4% compared to that in healthy controls. Collectively, our results suggested that the CCM1 mutation could potentially be a causative factor for FCCMs in the Chinese family and the reduction of CCM1 mRNA expression in the blood lymphocytes of the patients might be a potential biomarker for the diagnosis and prognosis of CCMs. Our findings expanded the spectrum of CCM mutations and helped to guide genetic counseling and early genetic diagnosis for at-risk family members.

First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations

Autosomal dominant cerebral cavernous malformations (CCM) are leaky vascular lesions that can cause epileptic seizures and stroke-like symptoms. Germline mutations in either CCM1, CCM2 or CCM3 are found in the majority of patients with multiple CCMs or a positive family history. Recently, the first copy number neutral inversion in CCM2 has been identified by whole genome sequencing in an apparently mutation-negative CCM family. We here asked the question whether further structural genomic rearrangements can be detected within NGS gene panel data of unsolved CCM cases. Hybrid capture NGS data of eight index patients without a pathogenic single nucleotide, indel or copy number variant were analyzed using two bioinformatics pipelines. In a 58-year-old male with multiple CCMs in his brain and spinal cord, we identified a 294 kb insertion within the coding sequence of CCM2. Fine mapping of the breakpoints, molecular cytogenetic studies, and multiplex ligation-dependent probe amplification verified that the structural variation was an inverted unbalanced insertion that originated from 1p12-p11.2. As this rearrangement disrupts exon 6 of CCM2 on 7p13, it was classified as pathogenic. Our study demonstrates that efforts to detect structural variations in known disease genes increase the diagnostic sensitivity of genetic analyses for well-defined Mendelian disorders.