Large Multigenerational Family Research Articles

Family-based Studies to Identify Genetic Variants That Cause Congenital Heart Defects

Congenital heart defects (CHDs) are the most common congenital abnormalities. Analysis of large multigenerational families has led to the identification of a number of genes for CHDs. However, identifiable variations in these genes are the cause of a small proportion of cases of CHDs, suggesting significant genetic heterogeneity. In addition, large families with CHDs are rare, making the identification of additional genes difficult. Next-generation sequencing technologies will provide an opportunity to identify more genes in the future. However, the significant genetic variation between individuals will present a challenge to distinguish between 'pathogenic' and 'benign' variants. We have demonstrated that the analysis of multiple individuals in small families using combinations of algorithms can reduce the number of candidate variants to a small, manageable number. Thus, the analysis of small nuclear families or even distantly related 'sporadic' cases may begin to uncover the 'dark matter' of CHD genetics.

Developmental Dysplasia of the Hip: Linkage Mapping and Whole Exome Sequencing Identify a Shared Variant in CX 3 CR 1 in All Affected Members of a Large Multigeneration Family

Developmental dysplasia of the hip (DDH) is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the femur, suboptimal joint function, and accelerated wear of the articular cartilage resulting in arthritis. DDH affects 1 in 1000 newborns in the United States; there are well-defined "pockets" of high prevalence in Japan, and in Italy and other Mediterranean countries. Although reasonably accurate for detecting gross forms of hip dysplasia, existing techniques fail to find milder forms of dysplasia. Undetected hip dysplasia is the leading cause of osteoarthritis of the hip in young individuals, causing over 40% of cases in this age group. A sensitive and specific test for DDH has remained a desirable yet elusive goal in orthopedics for a long time. A 72-member, four-generation affected family has been recruited, and DNA from its members retrieved. Genomewide linkage analysis revealed a 2.61-Mb candidate region (38.7-41.31 Mb from the p term of chromosome 3) co-inherited by all affected members with a maximum logarithm (base 10) of odds (LOD) score of 3.31. Whole exome sequencing and analysis of this candidate region in four severely affected family members revealed one shared variant, rs3732378, that causes a threonine (polar) to methionine (non-polar) alteration at position 280 in the transmembrane domain of CX3CR1. This mutation is predicted to have a deleterious effect on its encoded protein, which functions as a receptor for the ligand fractalkine. By Sanger sequencing this variant was found to be present in the DNA of all affected individuals and obligate heterozygotes. CX3CR1 mediates cellular adhesive and migratory functions and is known to be expressed in mesenchymal stem cells destined to become chondrocytes. A genetic risk factor that might be among the etiologic factors for the family in this study has been identified, along with other possible aggravating mutations shared by four severely affected family members. These findings might illuminate the molecular pathways affecting chondrocyte maturation and bone formation.

Congenital posterior pole cataract and adult onset dilating cardiomyopathy: expanding the phenotype of αB‐crystallinopathies

Mutations in the αB-crystallin gene (CRYAB) have been reported in desmin-related myopathies, with or without cardiac involvement. Mutations in this gene have also been documented in large multi-generation families with autosomal dominant congenital posterior pole cataract (CPPC). In these congenital cataract families no cardiac or muscular phenotype was reported. This report describes a family with an unusual read-through mutation in CRYAB, leading to the elongation of the normal αB-crystallin protein with 19 amino acid residues. Affected family members combine a CPPC with an adult onset dilated cardiomyopathy (DCM), thereby expanding the αB-crystallinopathy phenotype. Repolarisation abnormalities preceded the onset of cardiomyopathy and were already present in childhood. No skeletal myopathy was observed. This report illustrates that congenital cataract can be a prelude to more severe disease even outside the context of inborn errors of metabolism. The identification of a CRYAB mutation in this family supports the notion that mutations in this gene are a rare cause of genetically determined DCM. The combined congenital cataract/cardiomyopathy phenotype adds to our understanding of the complex phenotypic spectrum of αB-crystallinopathies.

Phenotypic presentation of the Ser63Del MPZ mutation

Mutations in MPZ cause CMT1B, the second most frequent cause of CMT1. Elegant studies with Ser63del mice suggest that Ser63del MPZ is retained in the ER where it activates the unfolded protein response (UPR) that contributes to the neuropathy. Clinical information about patients with this mutation is limited. We present clinical and electrophysiological data on a large multigenerational family with CMT1B caused by Ser63del MPZ. The patients have a classical CMT1 phenotype that is much less severe than that of patients with Arg98Cys MPZ that also activates the UPR. These results suggest that clinical presentation along cannot predict which MPZ mutations will be retained in the ER and activate the UPR.

DCM-Linked D230N Tropomyosin Mutation Results in Early Dilatation and Systolic Dysfunction in Mice

Recently, a study in two large multi-generational families described a familial dilated cardiomyopathy (DCM) caused by a single amino acid substitution Asp230Asn (D230N) in tropomyosin. These families demonstrated a unique bimodal disease distribution in which infants presented with a severe form of DCM, while adults presented with a mild to moderate clinical phenotype. To determine the biophysical consequences of this mutation on tropomyosin and its effects on regulatory function in the sarcomere, we employed circular dichroism and the regulated in vitro motility assay. We found that while this mutation does not affect overall thermal stability of tropomyosin, it has a profound effect on regulatory function. As previously shown in solution, the presence of the D230N mutation decreases the maximal velocity of filament sliding and calcium sensitivity of thin filament activation compared to wild type filaments. Additionally, the D230N mutation increases the cooperativity of myofilament activation. In order to further explore our biophysical observations and the physiologic effects of the D230N mutation, we created a transgenic murine model. In mice carrying the D230N tropomyosin mutation we found evidence of early dilatation and systolic dysfunction by echocardiogram in the absence of histological changes such as fibrosis or inflammatory cell invasion. Ultrastructural analysis of transgenic left ventricular tissue demonstrated z-disk alterations. Finally, preliminary studies on isolated myocytes from transgenic mice loaded with fura-2AM demonstrate no discernible differences in calcium transients compared to non-transgenic siblings suggesting that functional impairments are not due to calcium handling defects. Collectively, these studies suggest that the D230N mutation in tropomyosin is responsible for alterations in structure and function of the thin filament that result in a primary dilatation of the cardiac left ventricle. This work is supported by funding from the Children's Cardiomyopathy Foundation.

Abstract P248: The DCM-Causing D230N Tropomyosin Mutation Produces an Age-Dependent Phenotype in Mice that Is Influenced by Transgene Dosage

A recent study in two large multigenerational families demonstrated a novel mutation in tropomyosin (Tm), Asp230Asn (D230N) that caused DCM with a unique natural history resulting in a striking bimodal disease distribution. Infants and young children with the D230N Tm mutation presented with a severe, often fatal DCM while adults developed a mild to moderate clinical phenotype. Position 230 in tropomyosin is proximal to the C-terminal unwinding of tropomyosin that is essential for the Tm-Tm overlap and for the Tm-cardiac troponin T (cTnT) interaction. We hypothesized that the age-dependent remodeling is a result of temporal isoform switches in the closely linked Tm-binding partner cTnT. To directly address this hypothesis, we used the regulated in vitro motility assay to determine the biophysical effects of the D230N Tm mutation as well as the effects of cTnT isoform changes on the regulatory function of thin filaments. We have found that both wild type and D230N Tm filaments inhibit filament sliding at low calcium indicating that the D230N mutation does not completely disrupt regulation. However in the presence of high calcium the D230N Tm mutation significantly decreases the maximal velocity of filament sliding (3.790 ± 0.1333 microns/sec, n=98) as compared to the wild type filaments (4.900 ± 0.1044, microns/sec n=76). These findings support an altered Tm-cTnT interaction because at maximal calcium concentrations, the myofilament activation at the level of cardiac troponin is not properly transmitted to tropomyosin thus decreasing the activity of myosin-ATPase. In order to extend our biophysical observations and to provide translational insight, we generated a D230N Tm transgenic mouse model. In preliminary studies we demonstrate that at two months the D230N transgenic mice have evidence for early dilatation. In addition, the differences in ventricular remodeling were highly dependent on transgene dose. At six months, we observed dilatation of the ventricle and thinning of the walls compared to non-transgenic siblings. However, the differences were not as marked as those at the two-month time point. Collectively, these findings support an age-dependent DCM phenotype that is modulated by transgene dosage.

Hereditary hyperferritinemia-cataract syndrome in two large multigenerational American families

Hereditary hyperferritinemia cataract syndrome (HHCS), an autosomal-dominant disorder characterized by hyperferritinemia and bilateral cataracts, is caused by mutations in the iron-responsive element of the ferritin light chain (FTL) gene. The purpose of this study is to describe the genotypic and phenotypic manifestations of HHCS observed in 2 large sets of unrelated American families. Forty-five patients were recruited from 2 unrelated families. Each underwent ophthalmological and general physical evaluation as well as laboratory testing of serum ferritin, iron, transferrin saturation, and total iron binding capacity. Serum DNA was evaluated for mutations by DNA amplification and sequencing of the FTL gene. Numerous cortical and nuclear white opacities in a stellate pattern occurred in 22 affected individuals and were the only clinical manifestation of HHCS. Of the 22, 16 (73%) demonstrated >1.00 D of astigmatism. Genetic analysis revealed mutation G32A in Pedigree 1 and mutation G32T in Pedigree 2, both heterozygous and located in the iron-responsive element of the ferritin light chain mRNA. Serum ferritin levels of affected subjects ranged from 555 to 2,453 μg/L (normal range, 24-336 μg/L male, 11-307 μg/L female), with greater ferritin levels and more severe cataracts associated with mutation G32A. Most clinical and genetic findings from these families are consistent with previous reports of HHCS. Astigmatism, previously not associated with HHCS, was present in the majority. Ferritin levels and age of cataract surgery varied among subjects with both FTL gene mutations, suggesting that phenotypic variability is modulated by other genetic or environmental factors.

Clinical and neurophysiological investigation of a large family with dominant Charcot-Marie-Tooth type 2 disease with pyramidal signs

Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy of motor and sensory impairment with distal predominance. Atrophy and weakness of lower limbs are the first signs of the disease. It can be classified, with the aid of electromyography and nerve conduction studies, as demyelinating (CMT1) or axonal (CMT2). Clinical and neurophysiological investigation of a large multigenerational family with CMT2 with autosomal dominant mode of transmission. Fifty individuals were evaluated and neurophysiological studies performed in 22 patients. Thirty individuals had clinical signs of motor-sensory neuropathy. Babinski sign was present in 14 individuals. Neurophysiological study showed motor-sensory axonal polyneuropathy. The clinical and neurophysiological characteristics of this family does not differ from those observed with other forms of CMT, except for the high prevalence of Babinski sign.

An exceptional mutational event leading to Chanarin-Dorfman syndrome in a large consanguineous family

Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive metabolic disorder featuring congenital ichthyosis combined with pleiomorphic visceral manifestations associated with tissue accumulation of cytoplasmic lipid droplets. Mutations in the ABHD5 gene, encoding a crucial cofactor for adipose triglyceride lipase, have been found to underlie all CDS cases reported to date. The purposed of this study was to ascertain the genetic defect underlying CDS in a large multigenerational family. We used a combination of direct sequencing, reverse transcriptase-polymerase chain reaction (RT-PCR) and microsatellite marker genotyping to identify a novel CDS-causing mutation in ABHD5. Although no pathogenic mutation could be identified in the coding sequence of the ABHD5 gene, polymorphic marker genotyping analysis supported linkage to this gene locus. Accordingly, direct sequencing of RT-PCR amplification products generated from patient skin-derived total RNA, revealed in all four patients the presence of a 101 bp insertion between exon 3 and exon 4. Bioinformatic analysis and direct sequencing indicated that this insertion resulted from an exceptional mutational event, namely, the insertion of a LINE element into intron 3 of the ABHD5 gene, leading to aberrant splicing out of the mutant intron 3. Our results confirm genetic homogeneity in CDS and underscore the importance of RNA studies in the molecular diagnosis of genodermatoses.

New disease gene location and high genetic heterogeneity in idiopathic scoliosis

Idiopathic scoliosis (IS) is a spine disorder of unknown origin with 1.5-3% prevalence in the general population. Besides the large multifactorial-form sample of IS, there is a good evidence for the existence of a monogenic subgroup in which the disease is inherited in a dominant manner. However, results from literature suggest a strong heterogeneity in the locations of the mutated genes. Using a high-resolution genome-wide scan, we performed linkage analyses in three large multigenerational IS families compatible with dominant inheritance including 9-12 affected members or obligate carriers. In two of these families, our results suggested intra-familial genetic heterogeneity, whereas, in the other, we observed a perfect marker disease co-segregation in two regions at 3q12.1 and 5q13.3. We can state that one of these two locations is a novel IS disease gene locus, as the probability of having this perfect co-segregation twice by chance in the genome is very low (P=0.001). Lastly, in all three families studied, linkage to the previously mapped dominant IS loci on chromosomes 19p13.3, 17p11.2, 9q34, 17q25 and 18q is unlikely, confirming that there is a high genetic heterogeneity within the subgroup of dominant forms of IS.

Effects of the A(−115)G variant on CREB1 promoter activity in two brain cell lines: Interactions with gonadal steroids

Major depressive disorder (MDD) is a leading contributor to disease burden worldwide. Previous genetic studies have revealed significant evidence of linkage of the CREB1 region to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. Systematic resequencing of the CREB1 gene in affected members of these families has identified rare sequence variants at positions -656 and -115 that appear to cosegregate with unipolar mood disorders in two large multigenerational families and three small nuclear families, respectively. Results from previous transfection experiments that employed constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene support the hypothesis that the A(-656) allele contributes to the development of MDD in women by selectively increasing the activity of the CREB1 promoter in brain cell lines exposed to 17 β-estradiol. Analogous transfection experiments described in the current study revealed that the G(-115) promoter variant reduced promoter activity in CATH.a neuronal cells regardless of the hormonal environment, consistent with the observation that increased risk for unipolar mood disorders conferred by this allele was not limited by sex. The effects of CREB1 promoter variants on promoter activity, their influence on the development of mood disorders and related clinical features, and the interaction of their phenotypic expression with sex seem likely to be complex and allele-specific rather than a general property of the CREB1 locus. © 2010 Wiley-Liss, Inc.

A Mutation in SLC24A1 Implicated in Autosomal-Recessive Congenital Stationary Night Blindness

Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder that can be associated with impaired night vision. The last decade has witnessed huge progress in ophthalmic genetics, including the identification of three genes implicated in the pathogenicity of autosomal-recessive CSNB. However, not all patients studied could be associated with mutations in these genes and thus other genes certainly underlie this disorder. Here, we report a large multigeneration family with five affected individuals manifesting symptoms of night blindness. A genome-wide scan localized the disease interval to chromosome 15q, and recombination events in affected individuals refined the critical interval to a 10.41 cM (6.53 Mb) region that harbors SLC24A1, a member of the solute carrier protein superfamily. Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model. Expression analysis using mouse ocular tissues shows that Slc24a1 is expressed in the retina around postnatal day 7. In situ and immunohistological studies localized both SLC24A1 and Slc24a1 to the inner segment, outer and inner nuclear layers, and ganglion cells of the retina, respectively. Our data expand the genetic basis of CSNB and highlight the indispensible function of SLC24A1 in retinal function and/or maintenance in humans.

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Effects of Human Cardiac Troponin T Mutations Associated with Cardiomyopathy

Mutations in troponin, an important muscle protein complex, can result in cardiomyopathy by interfering with the normal muscle activity of the heart. Troponin T (TnT) is the largest subunit of troponin and is involved in binding the troponin complex to the thin filament. Investigation of two mutations associated with cardiomyopathy in TnT, I90M and R173Q, showed different physiological characteristics. The TnT I90M mutation was identified as the causative agent of familial hypertrophic cardiomyopathy (FHC) in a large multi-generational Chinese family and at least two family members with this mutation died of sudden cardiac death. Another mutation in TnT, R173Q, was identified as the underlying cause of dilated cardiomyopathy (DCM). Patients with the TnT R173Q mutation experienced prenatal onset DCM and supraventricular tachycardia at a young age. Functional troponin complexes containing wild-type or mutant TnT's demonstrated similar maximal actomyosin ATPase activity. The inhibitory ability of the troponin complexes containing the I90M mutation was significantly reduced relative to wild-type TnT. Most RCM mutations investigated to date showed a reduced ability to inhibit actomyosin ATPase activity but the RCM mutation, R173Q, did not affect the inhibitory ability of troponin. The mutations showed increased (I90M) and decreased (R173Q) calcium sensitivity of actomyosin ATPase activity consistent with what has been observed for most FHC and DCM mutations. The mutations reduced the rate of degradation of these proteins by calpain relative to wild-type TnT. Overall, these results suggest that although calcium sensitivity may be an indicator of the type of cardiomyopathy no clear trends in maximal or minimal ATPase activity exist that can be used to characterize DCM and FHC mutations.

Tumor Mapping in 2 Large Multigenerational Families With CYLD Mutations

To comprehensively ascertain the extent and severity of clinical features in affected individuals from 2 large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the 3 appendageal tumor predisposition syndromes (familial cylindromatosis, Brooke-Spiegler syndrome, and multiple familial trichoepitheliomas) known to be associated with such germline mutations. Interfamilial and intrafamilial observational study. Tertiary genetic and dermatology referral center. Thirty-four individuals recruited from 2 large multigenerational families with CYLD mutations. Clinical details, history, and tumor maps were obtained from all participants; in 18, the information was corroborated by detailed clinical examination. Tumor density, distribution and histologic findings, associated medical conditions, patient symptoms, and impact of disease on quality of life. The severity of penetrance and phenotype varied within families. Although an approximately equal female to male predisposition was noted, 5 women and 1 man (of 26 patients surveyed [23%]) had undergone total scalp removal. The average age at onset was 16 years (range, 8-30 years). Symptoms reported by affected patients included painful tumors (in 12 of 23 patients [52%] who answered the question), conductive deafness, and sexual dysfunction. Of the 26 surveyed patients, tumors were noted on the scalp in 21 (81%), on the trunk in 18 (69%), and in the pubic area in 11 (42%). Tumor mapping provided clinical evidence that correlated with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction. The burden of disease at sites other than the head and neck appears to be underreported in the literature and greatly affects quality of life. Differentiation between the clinical diagnoses has little prognostic or clinical utility in genetic counseling, even within individuals from the same family. Thus, we suggest an encompassing diagnosis of "CYLD cutaneous syndrome." Finally, the clinical distribution of tumors suggests that hormonal factors may play an important role in tumor induction in these patients.

2q37 as a Susceptibility Locus for Idiopathic Basal Ganglia Calcification (IBGC) in a Large South Tyrolean Family

Familial idiopathic basal ganglia calcification (FIBGC) is an inherited neurodegenerative disorder characterized by the accumulation of calcium deposits in different brain regions, particularly in the basal ganglia. FIBGC usually follows an autosomal dominant pattern of inheritance. Despite the mapping to chromosome 14q of a susceptibility locus for IBGC (IBCG1) in one family, this locus has been excluded in several others, demonstrating genetic heterogeneity in this disorder. The etiology of this disorder thus remains largely unknown. Using a large extended multigenerational Italian family from South Tyrol with 17 affected in a total of 56 members, we performed a genome-wide linkage analysis in which we were able to exclude linkage to the IBCG1 locus on chromosome 14q and obtain evidence of a novel locus on chromosome 2q37. Electronic supplementary material. The online version of this article (doi:10.1007/s12031-009-9287-3) contains supplementary material, which is available to authorized users.

The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family

Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. By using the Kaplan-Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a 'wait and scan' policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients.

Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations

Background:Mutations in the transforming growth factor β receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys–Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), aneurysms and...

Mitochondrial DNA G8363A mutation in the tRNA Lys gene: Clinical, biochemical and pathological study

The G8363A is a very rare mtDNA tRNA Lys gene mutation that has been associated to MERRF-like syndrome, cardiomyopathy or Leigh syndrome. Here, we describe the clinical and molecular features of a new large multigenerational family and we review the literature of cases with this mutation. In our family seven members presented a heterogeneous mitochondrial disease phenotype, from MERRF-like syndrome to isolated psychiatric disorder, associated with the G8363A mutation. The two probands are dizygotic twin sisters affected by mental retardation, neural deafness, myopathy, myoclonic epilepsy and ataxia. Twins' muscle biopsies showed a severe cytochrome c oxidase (COX) deficiency and ragged-red fibers. Their mitochondrial respiratory chain was defective in complexes I and IV in muscle. A severe reduction in complex IV activity was also observed in fibroblasts and myoblasts. Molecular analysis showed a G8363A transition in the mtDNA tRNA Lys gene. The mutation was almost homoplasmic (> 90%) in muscle and blood of the twins and heteroplasmic (55 ± 8%) in blood sample from affected maternal relatives. Based on our family data and the meta-analysis of the literature, we confirm that mutational load directly correlates with severity of the disease (severe vs mild/moderate phenotype; P = 0.00168) and with disease onset ( P < 0.00001). However the presence of several exceptions and overlaps among patients with different clinical severity limits the clinical usefulness of this observation. Although the pathogenicity of the G8363A mutation is well established, counselling is a difficult task for clinicians because of the large phenotypical variability. Our study contributes further data on the clinical spectrum and its relation with the level of G8363A tRNA Lys mtDNA mutation.

Phenotypic and Genetic Analysis of a Large Family With Migraine‐Associated Vertigo

To describe a large multigenerational family with migraine-associated vertigo (MAV) combining a detailed phenotypic and genetic analysis. Migraine-associated vertigo is said to be highly prevalent in the general population and, like other migraine syndromes, its etiology is felt to have a strong genetic component. However, so far, there have been no reports of large families with MAV. Detailed clinical study was conducted on a large multigenerational family with MAV. Genetic study using identical-by-descent analysis with dense single nucleotide polymorphism (SNP) arrays was performed to examine consistent inheritance pattern among the affecteds. Clinical features of MAV were variable although most had other migraine symptoms with at least some of their attacks. We did not find a region of the genome shared by all eight subjects with MAV indicating a polygenetic inheritance for MAV even in this single large family. A region on 11q shared by most affected females may contain a susceptibility allele for MAV that is expressed exclusively or predominantly by women.