A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype?

The prevalence of congenital heart defects is approximately 1% of all live births. Identifying the genes responsible for cardiac malformation is the first step to understand pathogenesis. Heterozygous mutations in the CSX/NKX2-5 (NKX2E) gene have been identified to cause atrial septal defect (ASD) and/or atrioventricular (AV) conduction disturbance in some families. However, there is great variability in expressivity of the phenotype between the patients with a CSX/NKX2-5 mutation.We screened four sporadic patients and three index cases of families with ASD and/or conduction defects. In one of them, a CSX/NKX2-5 mutation was identified. This novel mutation (p.Tyr256X) was inherited in a three-generation family causing five individuals to have cardiac anomalies ranging from ASD to arrhythmias. Interestingly, all the observed AV conduction disturbances were at the nodal level, manifesting first as an AV block of the first degree and evolving toward a second-degree block. Atrial fibrillation, previously reported in three individuals with CSX/NKX2-5 mutations, was observed in three patients.     

Incidence and outcome of arrhythmias and electrical disease in patients with Trisomy 18

Patients with Trisomy 18 have a high incidence of cardiac anomalies and are associated with early death. Because of early mortality, electrical system disease and arrhythmia has been difficult to delineate and the incidence remain unknown. We sought to describe the association and clinical outcomes of electrical system disease and cardiac tachy-arrhythmias in patients with Trisomy 18. This was a retrospective, single institutional study. All patients with Trisomy 18 were included in the study. Patient characteristics, congenital heart disease (CHD), conduction system and clinical tachy-arrhythmia data were collected on all patients. Outcomes including cardiac surgical interventions, electrical system interventions and death were collected until the time of study. Patients with tachy-arrhythmias/electrical system involvement were compared to those without to identify potential associated variables. A total of 54 patients with Trisomy 18 were included in analysis. The majority of patients was female and had associated CHD. AV nodal conduction system abnormalities with either first or second degree AV block were common (15%) as was QTc prolongation (37%). Tachy-arrhythmias were common with 22% of patients having at least one form of tachy-arrhythmia and associated with concomitant conduction system disease (p = 0.002). Tachy-arrhythmias were typically treatable with monitoring or medication with eventual resolution without need for procedural intervention. Although early death was common, there were no causes of death associated with tachy-arrhythmia or conduction system disease. In conclusion, patients with Trisomy 18 have a high incidence of conduction system abnormalities and burden of clinical tachy-arrhythmias. Although frequent, electrical system disease did not affect patient outcome or difficultly of care delivery.     

Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect

Recently, GATA4 and NKX2.5 were reported as the disease genes of atrial septal defect (ASD) but the relationship between the locations of their mutations and phenotypes is not clear. We analyzed GATA4 and NKX2.5 mutations in 16 familial ASD cases, including four probands with atrioventricular conduction disturbance (AV block) and two with pulmonary stenosis (PS), by PCR and direct sequencing, and examined their phenotypes clinically. Five mutations, including two GATA4 and three NKX2.5 mutations, were identified in 31.3% of the probands with ASD, and three of them were novel. The two GATA4 mutations in the probands without AV block were S52F and E359Xfs (c.1075delG) that was reported previously, and three NKX2.5 mutations in the probands with AV block were A88Xfs (c.262delG), R190C, and T178M. Additionally, we observed some remarkable phenotypes, i.e., dextrocardia with E359Xfs (c.1075delG) and cribriform type ASD with R190C, both of which are expected to be clues for further investigations. Furthermore, progressive, most severe AV block was closely related with a missense mutation in a homeodomain or with a nonsense/frame-shift mutation of NKX2.5 for which classification has not been clearly proposed. This pinpoints essential sites of NKX2.5 in the development of the conduction system.     

Pathological Aspects of Radiofrequency Catheter Ablation of the Canine Atrioventricular Node and Bundle of His

Radiofrequency catheter ablation of the atrioventricular (AV) node or bundle of His was performed in 12 adult mongrel dogs. The aim was to create chronic incomplete AV block (first- and second-degree AV block) and to examine the histopathology of the ablated lesions. However, the late electrophysiological results (2 4 weeks follow up) were various: normal in 2 dogs, mild PR prolongation (< 50%) in 2 dogs, first-degree AV block (PR prolongation a 50%) in 2 dogs, second degree AV block in 2 dogs, complete AV block in 4 dogs. The maximally ablated area (%) of the atrioventricular conduction system in serial histologic sections from dogs with these conditions was 69%, 75%, 89.5%, 95% and 99.5%, respectively. The number of intact conduction cells at the maximally ablated site varied from 6 to 30 in the four cases of incomplete AV block. The mean ablated volume (%) of either the AV node or penetrating His bundle correlated roughly with the degree of AV block. The ablated lesions were well demarcated and almost replaced by dense fibrous tissue at 4 weeks. Interruption (3 dogs) or thinning (1 dog) of the endocardial elastic lamellae was detected, in association with endocardial thickening (mean 913 μm). Endocardial thrombi were found in 3 dogs (2 fresh, 1 organized). We conclude that radiofrequency catheter ablation does not cause severe complicated lesions. Several possible conditions for creating chronic incomplete AV block are discussed. Acta Pathol Jpn 41: 487–498, 1991.     

Pathological aspects of radiofrequency catheter ablation of the canine atrioventricular node and bundle of His. With special reference to chronic incomplete atrioventricular block.

Radiofrequency catheter ablation of the atrioventricular (AV) node or bundle of His was performed in 12 adult mongrel dogs. The aim was to create chronic incomplete AV block (first- and second-degree AV block) and to examine the histopathology of the ablated lesions. However, the late electrophysiological results (2-4 weeks follow-up) were various: normal in 2 dogs, mild PR prolongation (less than 50%) in 2 dogs, first-degree AV block (PR prolongation greater than or equal to 50%) in 2 dogs, second-degree AV block in 2 dogs, complete AV block in 4 dogs. The maximally ablated area (%) of the atrioventricular conduction system in serial histologic sections from dogs with these conditions was 69%, 75%, 89.5%, 95% and 99.5%, respectively. The number of intact conduction cells at the maximally ablated site varied from 6 to 30 in the four cases of incomplete AV block. The mean ablated volume (%) of either the AV node or penetrating His bundle correlated roughly with the degree of AV block. The ablated lesions were well demarcated and almost replaced by dense fibrous tissue at 4 weeks. Interruption (3 dogs) or thinning (1 dog) of the endocardial elastic lamellae was detected, in association with endocardial thickening (mean 913 microns). Endocardial thrombi were found in 3 dogs (2 fresh, 1 organized). We conclude that radiofrequency catheter ablation does not cause severe complicated lesions. Several possible conditions for creating chronic incomplete AV block are discussed.     

Left anterior hemiblock in acute myocardial infarction. Incidence and clinical significance in relation to the presence of bundle branch block and to the absence of intraventricular conduction defects

The incidence of intraventricular conduction defects was examined retrospectively in 449 consecutive patients with acute myocardial infarction (AMI). The incidence of left anterior hemiblock (LAH), right bundle branch block (RBBB), left bundle branch block (LBBB) and RBBB+LAH was 12.2, 4.2, 3.8 and 2.5%, respectively. At least 24 patients (5.8%) developed LAH as a result of the AMI. LAH was present in 20% (33/164) of patients with anterior infarction, in 14% (18/131) of those with infarction of undetermined localization, and in 3% (4/143) of patients with diaphragm infarction. The incidence of complete atrioventricular (AV) block in patients with LAH was 6% and in patients with no intraventicular conduction defects 7%. In patients with RBBB, RBBB+LAH and LBBB, the incidence of complete AV block was 37, 45 and 18%, respectively. Severe pump failure occurred with the same low incidence in patients with LAH as in patients without intraventricular conduction defects, but was much more common in patients with complete bundle branch block (BBB). The mortality rate for patients with LAH was 22% and for patients with no intraventricular conduction defects 21%. In patients with RBBB, RBBB+LAH and LBBB, the mortality rates were 53, 55 and 53%, respectively. Patients with complete BBB had a higher age and a higher incidence of previous AMI than the others. Compared to patients with no intraventricular conduction defects, the presence of LAH did not increase the mortality rate, or the risk of developing severe heart failure or complete AV block, in contrast to the serious prognosis in patients with complete BBB.     

Complete atrioventricular block associated with lymphocytic myocarditis of the atrioventricular node in two young adult dogs

A histological investigation of the atrioventricular (AV) conduction system was performed in two young adult dogs with complete AV block. In both cases, infiltration of lymphocytes and plasma cells into the AV node and loss and disappearance of the conduction fibres were observed. Such inflammatory lesions of the AV conduction system were associated with complete AV block. The aetiology of these changes and the cause of its location at the AV node were not elucidated.     

Persistent atrioventricular block in Lyme borreliosis

Summary Cardiac manifestations are reported in 0.3%–4.0% of European patients withBorrelia burgdorferi (B.b.) infection. Usually symptoms disappear within 6 weeks. We report a case with persistent impairment of atrioventricular (AV) conduction. Diagnosis was confirmed by demonstration of IgM antibodies and increase of IgG antibody titers against B.b. in serum, by isolation of the spirochete from skin biopsy material and by the typical clinical combination of erythema migrans, Bannwarth syndrome (meningoradiculitis), and complete heart block. Despite immediate antibiotic therapy with ceftriaxone, first degree AV block and second degree block Wenckebach with atrial pacing at 100 beats/minute persisted for 2 years. We conclude, that Lyme carditis can cause long-standing or irreversible AV conduction defects despite adequate and early antimicrobial therapy.Abbreviations AV atrioventricular - AVt atrioventricular time - B. burgdorferi Borrelia burgdorferi - CSF cerebrospinal fluid - ECG electrocardiogram - ESR erythrocyte sedimentation rate - FRG Federal Republic of Germany - I. dammini/ricinus Ixodes dammini/ricinus - IgG immunoglobulin G - IgM immunoglobulin M     

自主神经对心脏房室传导调节的动态分析

尽管自主神经对心脏房室传导的作用报道很多，但自主神经对房室传导的动力学特性仍未被揭示。本实验通过模板匹配方法从His束电图检测A、H、V波并测量两心房间期(AA)、心房波与H波间期(AH)、H波与心室波间期(HV)和心房波与心室波间期(AV)，通过白噪声技术动力性刺激迷走神经、交感神经或心房起搏时AV间期的传递函数变化，研究动态自主神经刺激对房室传导的动态调节。结果如下：AV间期对迷走神经刺激呈一阶低通滤波性质，起搏时AV间期增益(13．2％)较未起搏时明显增高(4．6％，P＜0．05)；AV间期对交感神经刺激呈二阶低通滤波性质，起搏时AV间期增益(46％)较未起搏时明显增高(32％，P＜0．05)；动力性起搏心房，从间期与AV间期呈良好负相关。因此认为：(1)AV间期对迷走神经或交感神经刺激均呈现出低通滤波性质。(2)心脏的房室传导时间与心动周期长度呈线性负相关。心率的改变增强交感或迷走神经对房室传导的动力性作用，心率对房室传导的作用在迷走刺激时较交感刺激时强。这在房室传导对自主神经动力性调节的反应时保持相对稳定具有重要的生理意义。     

Mutational spectrum in the Ca(2+)--activated cation channel gene TRPM4 in patients with cardiac conductance disturbances

Very recently, mutations in the TRPM4 gene have been identified in four pedigrees as the cause of an autosomal dominant form of cardiac conduction disease. To determine the role of TRPM4 gene variations, the relative frequency of TRPM4 mutations and associated phenotypes was assessed in a cohort of 160 unrelated patients with various types of inherited cardiac arrhythmic syndromes. In eight probands with atrioventricular block or right bundle branch block--five familial cases and three sporadic cases--a total of six novel and two published TRPM4 mutations were identified. In patients with sinus node dysfunction, Brugada syndrome, or long-QT syndrome, no mutations were found. The novel mutations include six amino acid substitutions and appeared randomly distributed through predicted TRPM4 protein. In addition, eight polymorphic sites including two in-frame deletions were found. Mutations separated from polymorphisms by absence in control individuals and familial cosegregation in some families. In summary, TRPM4 gene mutations appear to play a major role in cardiac conduction disease but not for other related syndromes so far. The phenotypes are variable and clearly suggestive of additional factors modulating the disease phenotype in some patients.     

Structure-function relationship in the AV junction

In the normal heart, the atrioventricular node (AVN) is part of the sole pathway between the atria and ventricles. Under normal physiological conditions, the AVN controls appropriate frequency-dependent delay of contractions. The AVN also plays an important role in pathology: it protects ventricles during atrial tachyarrhythmia, and during sinoatrial node failure an AV junctional pacemaker can drive the heart. Finally, the AV junction provides an anatomical substrate for reentry. Using fluorescent imaging with voltage-sensitive dyes and immunohistochemistry, we have investigated the structure-function relationship of the AV junction during normal conduction, reentry, and junctional rhythm. We identified molecular and structural heterogeneity that provides a substrate for the dual-pathway AVN conduction. We observed heterogeneity of expression of three isoforms of connexins: Cx43, Cx45, and Cx40. We identified the site of origin of junctional rhythm at the posterior extension of the AV node in 79% (n = 14) of the studied hearts. This structure was similar to the compact AV node as determined by morphologic and molecular investigations. In particular, both the posterior extension and the compact node express the pacemaking channel HCN4 (responsible for the I(F) current) and neurofilament 160. In the rabbit heart, AV junction conduction, reentrant arrhythmia, and spontaneous rhythm are governed by heterogeneity of expression of several isoforms of gap junctions and ion channels. Uniform neurofilament expression suggests that AV nodal posterior extensions are an integral part of the cardiac pacemaking and conduction system. On the other hand, differential expression of Cx isoforms in this region provides an explanation of longitudinal dissociation, dual-pathway electrophysiology, and AV nodal reentrant arrhythmogenesis.     

A morphologic study on human conduction system of heart considering influences of some disorders of individuals

The authors have investigated the aging changes of the human AV node, AV bundle, and bundle branches considering the influences of various disorders of individuals upon these conduction tissues. These conduction tissues began to develop gradually from the infant stage and the development was completed by young adult stage. Aging changes of the conduction tissues were fat infiltration, fibrosis and elastosis, disappearance of muscle fiber, and general atrophy of the conduction tissues. They were thought to occur not only by aging but also by the influences of various disorders particularly of long-standing chronic diseases. Changes of the conduction tissues seem to be related with thickening and luminal narrowing of the AV nodal artery and superior ventricular septal arteries. Marked elastosis or atrophy was noted in the cases suffering from some long-standing disorder regardless of the sort of disorders. In the cases which were diagnosed as complete heart block clinically, destruction of the conduction tissues was extremely severe including those of the SA node.     

A MORPHOLOGIC STUDY ON HUMAN CONDUCTION SYSTEM OF HEART CONSIDERING INFLUENCES OF SOME DISORDERS OF INDIVIDUALS

The authors have investigated the aging changes of the human AV node, AV bundle, and bundle branches considering the influences of various disorders of individuals upon these conduction tissues. These conduction tissues began to develop gradually from the infant stage and the development was completed by young adult stage. Aging changes of the conduction tissues were fat infiltration, fibrosis and elastosis, disappearance of muscle fiber, and general atrophy of the conduction tissues. They were thought to occur not only by aging but also by the influences of various disorders particularly of longstanding chronic diseases. Changes of the conduction tissues seem to be related with thickening and luminal narrowing of the AV nodal artery and superior ventricular septal arteries. Marked elastosis or atrophy was noted in the cases suffering from some long-standing disorder regardless of the sort of disorders. In the cases which were diagnosed as complete heart block clinically, destruction of the conduction tissues was extremely severe including those of the SA node.     

Molecular mechanisms of congenital heart disease

BackgroundCongenital heart disease (CHD) is the most common type of birth defect. Despite the many advances in our understanding of cardiac development and many genes related to cardiac development identified, the fundamental etiology for the majority of cases of congenital heart disease remains unknown.MethodsThis review summarizes normal cardiac development, outlines the recent discoveries of the genetic causes of CHD, and provides possible strategies for exploring them.ResultsCHD is a multifactorial complex disease, with environmental and genetic factors playing important roles. A number of causative genes of selected congenital heart defects and genetic syndromes have been found. The molecular mechanisms of CHD may include mutations in components of the cardiac gene network, altered haemodynamics, regulatory pathway of cardiac genes, micro-RNA dysfunction, epigenetics, adult congenital heart diseases, and so on.ConclusionsThe molecular basis of CHD is an exciting and rapidly evolving field. The continuing advances in the understanding of the molecular mechanisms of CHD will hopefully result in improved genetic counseling and care of affected individuals and their families.     

Arrhythmias Presenting in Neonatal Lupus

Perfusion of human foetal heart with anti‐Ro/SSA antibodies induces transient heart block. Anti‐Ro/SSA antibodies may cross‐react with T‐ and L‐type calcium channels, and anti‐p200 antibodies may cause calcium to accumulate in rat heart cells. These actions may explain a direct electrophysiological effect of these antibodies. Congenital complete heart block is the more severe manifestation of so‐called “Neonatal Lupus”. In clinical practice, it is important to distinguish in utero complete versus incomplete atrioventricular (AV) block, as complete AV block to date is irreversible, while incomplete AV block has been shown to be potentially reversible after fluorinated steroid therapy. Another issue is the definition of congenital AV block, as cardiologists have considered congenital blocks detected months or years after birth. We propose as congenital blocks detected in utero or within the neonatal period (0–27 days after birth). The possible detection of first degree AV block in utero, with different techniques, might be a promising tool to assess the effects of these antibodies. Other arrhythmias have been described in NL or have been linked to anti‐Ro/SSA antibodies: first degree AV block, in utero and after birth, second degree (i.e. incomplete block), sinus bradycardia and QT prolongation, both in infants and in adults, ventricular arrhythmias (in adults). Overall, these arrhythmias have not a clinical relevance, but are important for research purposes.     

Pathogenesis of cardiac conduction disorders in children genetic and histopathologic aspects

Fetal dysrhythmias are usually transient. Abnormal fetal rates and rhythms during labor are "functional." Fetal dysrhythmias may be associated with congenital heart disease and fetal hydrops. Bradycardia is usually related to fetal distress; supraventricular tachycardia, atrial flutter, and atrial fibrillation may be associated with severe congestive heart failure. Ventricular fibrillation is rare in the fetus and infant and is usually associated with myocardial necrosis with perimembranous septal defect; the nonbranching atrioventricular (AV) bundle may have an aberrant position and result in cardiac arrhythmia. Wolff-Parkinson-White syndrome with conduction abnormalities and left ventricular hypertrophy (LVH) is due to an accessory pathway that bypasses the AV sulcus and results in faster conduction. Carnitine deficiency may be primary or secondary and may result in cardiac arrhythmia. Histiocytoid cardiomyopathy is characterized by cardiomegaly, incessant ventricular tachycardia, and frequently sudden death. Arrhythmogenic right ventricular dysplasia (ARVD) results in ventricular tachycardia and left bundle branch block. Noncompaction of the left ventricle predisposes to potentially fatal arrhythmias. Long Q-T syndromes (LQTS) are a heterogeneous group of disorders with many genetic mutations. Brugada syndrome is an autosomal dominant trait with right bundle branch block and ST elevation. Barth syndrome is an X-linked disorder with dilated cardiomyopathy, cyclic neutropenia and skeletal myopathy. Hypertrophic cardiomyopathy in infancy may be related to metabolic diseases, particularly glycogen storage diseases; the familial form predisposes to sudden death. Arrhythmias following cardiac surgery may occur after closure of a ventricular septal defect (VSD) or damage to the conduction system.     

Caution in interpretation of disease causality for heterozygous loss-of-function variants in the MYH8 gene associated with autosomal dominant disorder

To date, the NM_002472.2(MYH8):c.2021G>A (p.Arg674Gln) missense variant in the MYH8 gene is the only known genetic change in individuals with autosomal dominant trismus-pseudocamptodactyly syndrome with unknown molecular mechanism. Next-generation sequencing (NGS), including targeted gene panels and whole-exome sequencing, is routinely performed in many clinical diagnostic laboratories as standard-of-care testing aimed at identifying disease-causing genomic variants. Whole-exome sequencing has revealed loss-of-function variants in the MYH8 gene. To properly classify the MYH8 loss-of-function variants, we either retrieved them from public databases or retrospectively collected them from individuals genetically tested by custom NGS panels or by whole-exome sequencing and confirmed using Sanger sequencing. We further evaluated the respective clinical presentations of these individuals with the MYH8 loss-of-function variants. Heterozygous loss-of-function variants in the MYH8 gene were detected in 16 individuals without trismus-pseudocamptodactyly syndrome. Four of these 16 individuals had a pathogenic or likely pathogenic variant detected in another gene that could explain their clinical presentation. Moreover, there are ∼100 MYH8 heterozygous protein-truncating and splice site variants in the ExAC database in different populations. Our results, combined with the population data, indicate that loss-of-function variants in the MYH8 gene do not cause autosomal dominant trismus-pseudocamptodactyly syndrome, and the clinical significance of these variants remains unknown at present. This result highlights the importance of considering the molecular mechanism of disease, variants published in the medical literature, and population genomic data for the correct interpretation of loss-of-function variants in genes associated with autosomal dominant diseases.     

Invasive electrophysiological evaluation of patients with sleep apnoea-associated ventricular asystole—methods and preliminary results

SUMMARY  Twelve patients (aged 48 ± 12 y) with ventricular asystole of >3s due to complete atrioventricular (AV) block ( n = 8), sinoatrial (SA) block or sinus node arrest ( n = 3) or both ( n = 1) associated with obstructive sleep apnoea underwent invasive electrophysiological evaluation of sinus node function and AV conduction properties before and after administration of atropine (0.02 mg kg^-1). Ventricular asystole lasted for 5.9 ± 2.8 s (range 3.1–13 s). Sinus node function was assessed by measurement of sinus node recovery time, sinoatrial conduction time, and the response of sinus rate to atropine. Parameters of AV-conduction assessment included AH- and HV-intervals, AV- and VA-Wenckebach periods, and effective refractory period of the AV node before and after atropine. Sinus node function was normal in 11 of the 12 study patients and moderately abnormal in 1 patient. AV-nodal function was normal in 8 patients and moderately abnormal in 4 patients. A slightly prolonged HV-interval (59–63 ms) was present in 6 patients. Intra- or infra His block was not observed in any patient. In conclusion, normal or only moderately abnormal electrophysiological findings in patients with sleep apnoea-associated ventricular asystole suggest that a neurally mediated cardioinhibitory reflex may cause ventricular asystole in these patients. This sleep apnoea-triggered 'vasovagal' reflex may unmask pre-existing mild to moderate structural abnormalities of the AV conduction system.     

Investigations into Ro-specific antibody-associated congenital cardiac conduction defects

Summary Forty-two babies with different congenital cardiac conduction defects, and in 12 cases the mothers, were tested for autoantibodies to Ro, La, U₁RNP and Sm. Ro-specific antibodies were detected most frequently. They were to be found in 16 sera from infants and in 8 maternal serum samples. The occurrence of anti-Ro was associated preferentially with several atrioventricular conduction blocks. The sex relation of anti-Ro associated congential heart block did not show a typical preference (6 male/10 female). At the time of giving birth, 5 anti- Ro-positive mothers did not have any clinical symptoms of rheumatic autoimmune diseases. Three of them had a first degree atrioventricular block. Our findings indicate that all pregnant women at risk for anti-Ro like connective tissue disease or cardiac conduction defects should be tested for these autoantibodies because of the suspicion of cardiac conduction abnormalities in the offspring. Anti-Ro-positive infants should be examined for structural heart disease by echocardiography.Abbreviations anti-EBV VCA IgG anti-viral capsid antigens immunoglobulin G - AV atrioventricular - CHB congenital heart block - CIE counter immunoelectrophoresis - EBV Epstein-Barr virus - NLE neonatal lupus erythematosus - SLE systemic lupus erythematosus     

Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age- related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G- >T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G- >A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.