Judith M.A. Verhagen

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2–24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.

Phenotypic variability of atypical 22q11.2 deletions not including TBX1

Interstitial deletions of the chromosome 22q11.2 region are the most common microdeletions in humans. The TBX1 gene is considered to be the major candidate gene for the main features in 22q11.2 deletion syndrome, including congenital heart malformations, (para)thyroid hypoplasia, and craniofacial abnormalities. We report on eight patients with atypical deletions of chromosome 22q11.2. These deletions comprise the distal part of the common 22q11.2 deleted region but do not encompass the TBX1 gene. Ten similar patients with overlapping distal 22q11.2 deletions have been reported previously. The clinical features of these patients are described and compared to those found in the classic 22q11.2 deletion syndrome. We discuss the possible roles of a position effect or haploinsufficiency of distally located genes (e.g., CRKL) in the molecular pathogenesis of the 22q11.2 deletion syndrome.

Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations.

The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual facial morphology, variable intellectual disabilities and infrequently malformations. The syndrome is heterogeneous as mutations in the gene CCBE1 have been found responsible for the syndrome in only a subset of patients. We investigated whether it would be possible to predict the presence of a CCBE1 mutation based on phenotype by collecting clinical data of patients diagnosed with HS, with or without a CCBE1 mutation. We report here the results of 13 CCBE1 positive patients, 16 CCBE1 negative patients, who were clinically found to have classical HS, and 8 patients in whom the diagnosis was considered possible, but not certain, and in whom no CCBE1 mutation was identified. We found no statistically significant phenotypic differences between the 2 groups with the clinical HS phenotype, although the degree of lymphatic dysplasia tended to be more pronounced in the mutation positive group. We also screened 158 patients with less widespread and less pronounced forms of lymphatic dysplasia for CCBE1 mutations, and no mutation was detected in this group. Our results suggest that (1) CCBE1 mutations are present only in patients with a likely clinical diagnosis of HS, and not in patients with less marked forms of lymphatic dysplasia, and (2) that there are no major phenotypic differences between HS patients with or without CCBE1 mutations.

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.

Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy

BACKGROUND Cardiomyopathies are usually inherited and predominantly affect adults, but they can also present in childhood. Although our understanding of the molecular basis of pediatric cardiomyopathy has improved, the underlying mechanism remains elusive in a substantial proportion of cases. OBJECTIVES This study aimed to identify new genes involved in pediatric cardiomyopathy. METHODS The authors performed homozygosity mapping and whole-exome sequencing in 2 consanguineous families with idiopathic pediatric cardiomyopathy. Sixty unrelated patients with pediatric cardiomyopathy were subsequently screened for mutations in a candidate gene. First-degree relatives were submitted to cardiac screening and cascade genetic testing. Myocardial samples from 2 patients were processed for histological and immunohistochemical studies. RESULTS We identified 5 patients from 3 unrelated families with pediatric cardiomyopathy caused by homozygous truncating mutations in ALPK3, a gene encoding a nuclear kinase that plays an essential role in early differentiation of cardiomyocytes. All patients with biallelic mutations presented with severe hypertrophic and/or dilated cardiomyopathy in utero, at birth, or in early childhood. Three patients died from heart failure within the first week of life. Moreover, 2 of 10 (20%) heterozygous family members showed hypertrophic cardiomyopathy with an atypical distribution of hypertrophy. Deficiency of alpha-kinase 3 has previously been associated with features of both hypertrophic and dilated cardiomyopathy in mice. Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling. CONCLUSIONS Biallelic truncating mutations in the newly identified gene ALPK3 give rise to severe, early-onset cardiomyopathy in humans. Our findings highlight the importance of transcription factor pathways in the molecular mechanisms underlying human cardiomyopathies.

An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome

Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and multiple congenital anomalies, including short stature, peculiar facial appearance, skeletal anomalies, a variety of visceral malformations and abnormal dermatoglyphic patterns. We describe a case of Kabuki syndrome presenting with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. This report demonstrates that clinical follow-up and molecular genetic testing can be useful for establishing the correct diagnosis.

Phenotypic Variability Associated with a Large Recurrent 1q21.1 Microduplication in a Three-Generation Family

Recurrent copy number variants of the q21.1 region of chromosome 1 have been associated with variable clinical features, including developmental delay, mild to moderate intellectual disability, psychiatric and behavioral problems, congenital heart malformations, and craniofacial abnormalities. A subset of individuals is clinically unaffected. We describe a unique 3-generation family with a large recurrent 1q21.1 microduplication (BP2-BP4). Our observations underline the incomplete penetrance and phenotypic variability of this rearrangement. We also confirm the association with congenital heart malformations, chronic depression, and anxiety. Furthermore, we report a broader range of dysmorphic features. The extreme phenotypic heterogeneity observed in this family suggests that additional factors modify the clinical phenotype.

Incidental Finding of Alpha-Methylacyl-CoA Racemase Deficiency in a Patient With Oculocutaneous Albinism Type 4

Genome‐wide studies may lead to the discovery of genetic variants of potential clinical importance beyond the aims of the study. We performed single nucleotide polymorphism array analysis in a boy with oculocutaneous albinism to identify copy‐neutral regions of homozygosity harboring genes involved in melanin biosynthesis. An unanticipated homozygous deletion of chromosome 5p13.3 was discovered, encompassing not only the OCA gene SLC45A2, but also four additional genes. This led to an unexpected presymptomatic diagnosis of alpha‐methylacyl‐CoA racemase deficiency in the same patient.

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository

&NA; The cause of PHACE syndrome is unknown. In a study of 218 patients, we examined potential prenatal risk factors for PHACE syndrome. Rates of pre‐eclampsia and placenta previa in affected individuals were significantly greater than in the general population. No significant risk factor differences were detected between male and female subjects.