MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset.

INTRODUCTION: The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect. METHODS: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort. RESULTS: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8-74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients. CONCLUSION: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30 years.

KBTBD13 is a novel cardiomyopathy gene.

KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.

Titin Circular RNAs Create a Back-Splice Motif Essential for SRSF10 Splicing.

BACKGROUND: TTN (Titin), the largest protein in humans, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to the cardiomyocyte. Mutations that disrupt the TTN transcript are the most frequent cause of hereditary heart failure. We showed before that TTN produces a class of circular RNAs (circRNAs) that depend on RBM20 to be formed. In this study, we show that the back-splice junction formed by this class of circRNAs creates a unique motif that binds SRSF10 to enable it to regulate splicing. Furthermore, we show that one of these circRNAs (cTTN1) distorts both localization of and splicing by RBM20. METHODS: We calculated genetic constraint of the identified motif in 125 748 exomes collected from the gnomAD database. Furthermore, we focused on the highest expressed RBM20-dependent circRNA in the human heart, which we named cTTN1. We used shRNAs directed to the back-splice junction to induce selective loss of cTTN1 in human induced pluripotent stem cell-derived cardiomyocytes. RESULTS: Human genetics suggests reduced genetic tolerance of the generated motif, indicating that mutations in this motif might lead to disease. RNA immunoprecipitation confirmed binding of circRNAs with this motif to SRSF10. Selective loss of cTTN1 in human induced pluripotent stem cell-derived cardiomyocytes induced structural abnormalities, apoptosis, and reduced contractile force in engineered heart tissue. In line with its SRSF10 binding, loss of cTTN1 caused abnormal splicing of important cardiomyocyte SRSF10 targets such as MEF2A and CASQ2. Strikingly, loss of cTTN1 also caused abnormal splicing of TTN itself. Mechanistically, we show that loss of cTTN1 distorts both localization of and splicing by RBM20. CONCLUSIONS: We demonstrate that circRNAs formed from the TTN transcript are essential for normal splicing of key muscle genes by enabling splice regulators RBM20 and SRSF10. This shows that the TTN transcript also has regulatory roles, besides its well-known signaling and structural function. In addition, we demonstrate that the specific sequence created by the back-splice junction of these circRNAs has important functions. This highlights the existence of functionally important sequences that cannot be recognized as such in the human genome but provides an as-yet unrecognized source for functional sequence variation.

A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation.

This study shows that gain-of-function variants in KLHL24 causing EBS and DCM, do not only originate in the start-codon and suggest that any nonsense-inducing variant affecting nucleotides c.4_84 will likely cause the same effect on protein level and a similar potential lethal phenotype.

RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling.

BACKGROUND: Mutations in RBM20 (RNA-binding motif protein 20) cause a clinically aggressive form of dilated cardiomyopathy, with an increased risk of malignant ventricular arrhythmias. RBM20 is a splicing factor that targets multiple pivotal cardiac genes, such as Titin (TTN) and CAMK2D (calcium/calmodulin-dependent kinase II delta). Aberrant TTN splicing is thought to be the main determinant of RBM20-induced dilated cardiomyopathy, but is not likely to explain the increased risk of arrhythmias. Here, we investigated the extent to which RBM20 mutation carriers have an increased risk of arrhythmias and explore the underlying molecular mechanism. METHODS: We compared clinical characteristics of RBM20 and TTN mutation carriers and used our previously generated Rbm20 knockout (KO) mice to investigate downstream effects of Rbm20-dependent splicing. Cellular electrophysiology and Ca2+ measurements were performed on isolated cardiomyocytes from Rbm20 KO mice to determine the intracellular consequences of reduced Rbm20 levels. RESULTS: Sustained ventricular arrhythmias were more frequent in human RBM20 mutation carriers than in TTN mutation carriers (44% versus 5%, respectively, P=0.006). Splicing events that affected Ca2+- and ion-handling genes were enriched in Rbm20 KO mice, most notably in the genes CamkIIδ and RyR2. Aberrant splicing of CamkIIδ in Rbm20 KO mice resulted in a remarkable shift of CamkIIδ toward the δ-A isoform that is known to activate the L-type Ca2+ current ( ICa,L). In line with this, we found an increased ICa,L, intracellular Ca2+ overload and increased sarcoplasmic reticulum Ca2+ content in Rbm20 KO myocytes. In addition, not only complete loss of Rbm20, but also heterozygous loss of Rbm20 increased spontaneous sarcoplasmic reticulum Ca2+ releases, which could be attenuated by treatment with the ICa,L antagonist verapamil. CONCLUSIONS: We show that loss of Rbm20 disturbs Ca2+ handling and leads to more proarrhythmic Ca2+ releases from the sarcoplasmic reticulum. Patients that carry a pathogenic RBM20 mutation have more ventricular arrhythmias despite a similar left ventricular function, in comparison with patients with a TTN mutation. Our experimental data suggest that RBM20 mutation carriers may benefit from treatment with an ICa,L blocker to reduce their arrhythmia burden.

Myofilament Remodeling and Function Is More Impaired in Peripartum Cardiomyopathy Compared with Dilated Cardiomyopathy and Ischemic Heart Disease.

Peripartum cardiomyopathy (PPCM) and dilated cardiomyopathy (DCM) show similarities in clinical presentation. However, although DCM patients do not recover and slowly deteriorate further, PPCM patients show either a fast cardiac deterioration or complete recovery. The aim of this study was to assess if underlying cellular changes can explain the clinical similarities and differences in the two diseases. We, therefore, assessed sarcomeric protein expression, modification, titin isoform shift, and contractile behavior of cardiomyocytes in heart tissue of PPCM and DCM patients and compared these with nonfailing controls. Heart samples from ischemic heart disease (ISHD) patients served as heart failure control samples. Passive force was only increased in PPCM samples compared with controls, whereas PPCM, DCM, and ISHD samples all showed increased myofilament Ca2+ sensitivity. Length-dependent activation was significantly impaired in PPCM compared with controls, no impairment was observed in ISHD samples, and DCM samples showed an intermediate response. Contractile impairments were caused by impaired protein kinase A (PKA)-mediated phosphorylation because exogenous PKA restored all parameters to control levels. Although DCM samples showed reexpression of EH-myomesin, an isoform usually only expressed in the heart before birth, PPCM and ISHD did not. The lack of EH-myomesin, combined with low PKA-mediated phosphorylation of myofilament proteins and increased compliant titin isoform, may explain the increase in passive force and blunted length-dependent activation of myofilaments in PPCM samples.

Pseudodominant inheritance pattern in a family with CMT2 caused by GDAP1 mutations.

We report a family in which an autosomal dominantly inherited Charcot-Marie-Tooth (CMT) disease type 2 was suspected. The affected family members (proband, sister, father, and paternal aunt) showed intrafamilial clinical variability. The proband needed walking aids since adolescence because of generalized muscle weakness. The sister showed the same symptoms although to a lesser extent. The father and paternal aunt had foot deformity and atrophy of lower legs. A homozygous GDAP1 mutation was found in the proband and in the sister. Further testing showed compound heterozygous GDAP1 mutations in the father and paternal aunt. In this CMT2 family with a pseudodominant inheritance pattern DNA-diagnostics revealed the presence of both homozygous and compound heterozygous GDAP1 mutations. We recommend including multiple family members in genetic studies on CMT families.

Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families.

PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. METHODS: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested. RESULTS: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)). CONCLUSION: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.Genet Med 18 9, 914-923.

Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy.

AIM: Peripartum cardiomyopathy (PPCM) can be an initial manifestation of familial dilated cardiomyopathy (DCM). We aimed to identify mutations in families that could underlie their PPCM and DCM. METHODS AND RESULTS: We collected 18 families with PPCM and DCM cases from various countries. We studied the clinical characteristics of the PPCM patients and affected relatives, and applied a targeted next-generation sequencing (NGS) approach to detect mutations in 48 genes known to be involved in inherited cardiomyopathies. We identified 4 pathogenic mutations in 4 of 18 families (22%): 3 in TTN and 1 in BAG3. In addition, we identified 6 variants of unknown clinical significance that may be pathogenic in 6 other families (33%): 4 in TTN, 1 in TNNC1, and 1 in MYH7. Measurements of passive force in single cardiomyocytes and titin isoform composition potentially support an upgrade of one of the variants of unknown clinical significance in TTN to a pathogenic mutation. Only 2 of 20 PPCM cases in these families showed the recovery of left ventricular function. CONCLUSION: Targeted NGS shows that potentially causal mutations in cardiomyopathy-related genes are common in families with both PPCM and DCM. This supports the earlier finding that PPCM can be part of familial DCM. Our cohort is particularly characterized by a high proportion of TTN mutations and a low recovery rate in PPCM cases.

Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy.

A cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy was previously reported in three Dutch families. Here we report the genetic cause of this disorder. Multipoint parametric linkage analysis of six Dutch patients identified a homozygous region of 2.1 Mb on chromosome 12, which was shared between all Dutch patients, with a log of odds score of 10.82. Sequence analysis of the entire linkage region resulted in the identification of a homozygous mutation in the last acceptor splice site of the myosin regulatory light chain 2 gene (MYL2) as the genetic cause. MYL2 encodes a myosin regulatory light chain (MLC-2V). The myosin regulatory light chains bind, together with the essential light chains, to the flexible neck region of the myosin heavy chain in the hexameric myosin complex and have a structural and regulatory role in muscle contraction. The MYL2 mutation results in use of a cryptic splice site upstream of the last exon causing a frameshift and replacement of the last 32 codons by 20 different codons. Whole exome sequencing of an Italian patient with similar clinical features showed compound heterozygosity for two other mutations affecting the same exon of MYL2, also resulting in mutant proteins with altered C-terminal tails. As a consequence of these mutations, the second EF-hand domain is disrupted. EF-hands, assumed to function as calcium sensors, can undergo a conformational change upon binding of calcium that is critical for interactions with downstream targets. Immunohistochemical staining of skeletal muscle tissue of the Dutch patients showed a diffuse and weak expression of the mutant protein without clear fibre specificity, while normal protein was absent. Heterozygous missense mutations in MYL2 are known to cause dominant hypertrophic cardiomyopathy; however, none of the parents showed signs of cardiomyopathy. In conclusion, the mutations in the last exon of MYL2 are responsible for a novel autosomal recessive lethal myosinopathy due to defects changing the C-terminal tail of the ventricular form of the myosin regulatory light chain. We propose 'light chain myopathy' as a name for this MYL2-associated myopathy.

Targeted next-generation sequencing can replace Sanger sequencing in clinical diagnostics.

Mutation detection through exome sequencing allows simultaneous analysis of all coding sequences of genes. However, it cannot yet replace Sanger sequencing (SS) in diagnostics because of incomplete representation and coverage of exons leading to missing clinically relevant mutations. Targeted next-generation sequencing (NGS), in which a selected fraction of genes is sequenced, may circumvent these shortcomings. We aimed to determine whether the sensitivity and specificity of targeted NGS is equal to those of SS. We constructed a targeted enrichment kit that includes 48 genes associated with hereditary cardiomyopathies. In total, 84 individuals with cardiomyopathies were sequenced using 151 bp paired-end reads on an Illumina MiSeq sequencer. The reproducibility was tested by repeating the entire procedure for five patients. The coverage of ≥30 reads per nucleotide, our major quality criterion, was 99% and in total ∼21,000 variants were identified. Confirmation with SS was performed for 168 variants (155 substitutions, 13 indels). All were confirmed, including a deletion of 18 bp and an insertion of 6 bp. The reproducibility was nearly 100%. We demonstrate that targeted NGS of a disease-specific subset of genes is equal to the quality of SS and it can therefore be reliably implemented as a stand-alone diagnostic test.

Pathogenic variants in three families with distal muscle involvement.

Three families suspected of distal hereditary motor neuropathy underwent genetic screening with the aim to identify the molecular defect underlying the disease. The description of the identification reflects the shift in molecular diagnostics that was made during the last decades. Our candidate gene approach yielded a known pathogenic variant in BSCL2 (p.Asn88Ser) in one family, and via a CMT-capture, in HSPB1 (p.Arg127Trp), in addition to five other variations in Charcot-Marie-Tooth-related genes in the proband of the second family. In the third family, using whole exome sequencing, followed by linkage-by-location, a three base pair deletion in exon 33 of MYH7 (p.Glu1508del) was found, a reported pathogenic allele albeit for a myopathy. After identification of the causative molecular defect, cardiac examination was performed for patients of the third family and this demonstrated abnormalities in three out of five affected family members. Heterogeneity and expansion of clinical phenotypes beyond known characteristics requires a wider set of genes to be screened. Whole exome/genome analysis with limited prior clinical information may therefore be used to precede a detailed clinical evaluation in cases of large families, preventing screening of a too narrow set of genes, and enabling the identification of novel disease-associated genes. In our cases, the variants had been reported, and co-segregation analysis confirmed the molecular diagnosis.

Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension.

Purpose: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families. Methods: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis. Results: We identified 2 rare biallelic variants in CAPNS1, encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH. Conclusion: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered.

Legius syndrome in fourteen families.

Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome.

Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy.

BACKGROUND: Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the spectrum of familial DCM, presenting in the peripartum period. METHODS AND RESULTS: We reviewed our database of 90 DCM families, focusing specifically on the presence of PPCM patients. Then, in a reverse approach, we reviewed 10 PPCM patients seen in our clinic since the early 1990s and performed cardiological screening of the first-degree relatives of 3 PPCM patients who did not show a full recovery. Finally, we analyzed the genes known to be most commonly involved in DCM in the PPCM patients. We identified a substantial number (5 of 90, 6%) of DCM families with PPCM patients. Second, cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed undiagnosed DCM in all 3 families. Finally, genetic analyses revealed a mutation (c.149A>G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case. CONCLUSIONS: Our findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. This may have important implications for cardiological screening in such families.

The yield of risk stratification for sudden cardiac death in hypertrophic cardiomyopathy myosin-binding protein C gene mutation carriers: focus on predictive screening.

AIMS: We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM) and of risk factors for sudden cardiac death (SCD) at the first cardiological evaluation after predictive genetic testing in asymptomatic carriers of an MYBPC3 gene mutation. METHODS AND RESULTS: Two hundred and thirty-five mutation carriers were cardiologically evaluated on the presence of HCM and risk factors. A clinical diagnosis of HCM was made in 53 carriers (22.6%). Disease penetrance at 65 years was incomplete for all types of MYBPC3 gene mutations. Women were affected less often than men (15 and 32% respectively, P = 0.003) and disease penetrance was lower in females than in males (13 and 30% at 50 years, respectively, P = 0.024). One risk factor was present in 87 carriers and 9 had two or more risk factors. Twenty-five carriers (11%) with one or more risk factors and manifest HCM could be at risk for SCD. CONCLUSION: At first cardiological evaluation almost one-quarter of asymptomatic carriers was diagnosed with HCM. Risk factors for SCD were frequently present and 11% of carriers could be at risk for SCD. Predictive genetic testing in HCM families and frequent cardiological evaluation on the presence of HCM and risk factors for SCD are justified until advanced age.

The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.

Background - Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently. Methods - We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca2+ transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants. Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures. Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes.

KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.

Heritability in genetic heart disease: the role of genetic background.

Background: Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or 'modifier genes'. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins. Methods: We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy. Results: Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy. Conclusions: Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.