Amber Boys

Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion

Background: Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. At present, two genes have been identified to cause PH when mutated. Mutations in FLNA (Xq28) and ARFGEF2 (20q13) are responsible for X-linked bilateral PH and a rare autosomal recessive form of PH with microcephaly. Chromosomal rearrangements involving the 1p36, 5p15, and 7q11 regions have also been reported in association with PH but the genes implicated remain unknown. Fourteen additional distinct anatomoclinical PH syndromes have been described, but no genetic insights into their causes have been gleaned. Methods: We report the clinical and imaging features of three unrelated patients with epilepsy, mental retardation, and bilateral PH in the walls of the temporal horns of the lateral ventricles, associated with a de novo deletion of the 5q14.3-15 region. We used microarray-based comparative genomic hybridization to define the boundaries of the deletions. Results: The three patients shared a common deleted region spanning 5.8 Mb and containing 14 candidate genes. Conclusion: We identified a new syndrome featuring bilateral periventricular heterotopia (PH), mental retardation, and epilepsy, mapping to chromosome 5q14.3-q15. This observation reinforces the extreme clinical and genetic heterogeneity of PH. Array comparative genomic hybridization is a powerful diagnostic tool for characterizing causative chromosomal rearrangements of limited size, identifying potential candidate genes for, and improving genetic counseling in, malformations of cortical development.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

A novel AMPD2 mutation outside the AMP deaminase domain causes pontocerebellar hypoplasia type 9

A Novel AMPD2 Mutation Outside the AMP Deaminase Domain Causes Pontocerebellar Hypoplasia Type 9 Ashley P. L. Marsh, Patrick Yap, Tiong Tan, Kate Pope, Susan M. White, Belinda Chong, George Mcgillivray, Amber Boys, Sarah E. M. Stephenson, Richard J. Leventer, Zornitza Stark, and Paul J. Lockhart* Bruce Lefroy Centre For Genetic Health Research, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Genetic Health Service New Zealand (Northern Hub), Auckland City Hospital, Auckland, New Zealand Neuroscience Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Department of Neurology, University of Melbourne, Royal Children’s Hospital, Parkville, Victoria, Australia

Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome.

Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome.

Deep phenotyping of speech and language skills in individuals with 16p11.2 deletion

Recurrent deletions of a ~600-kb region of 16p11.2 have been associated with a highly penetrant form of childhood apraxia of speech (CAS). Yet prior findings have been based on a small, potentially biased sample using retrospectively collected data. We examine the prevalence of CAS in a larger cohort of individuals with 16p11.2 deletion using a prospectively designed assessment battery. The broader speech and language phenotype associated with carrying this deletion was also examined. 55 participants with 16p11.2 deletion (47 children, 8 adults) underwent deep phenotyping to test for the presence of CAS and other speech and language diagnoses. Standardized tests of oral motor functioning, speech production, language, and non-verbal IQ were conducted. The majority of children (77%) and half of adults (50%) met criteria for CAS. Other speech outcomes were observed including articulation or phonological errors (i.e., phonetic and cognitive-linguistic errors, respectively), dysarthria (i.e., neuromuscular speech disorder), minimal verbal output, and even typical speech in some. Receptive and expressive language impairment was present in 73% and 70% of children, respectively. Co-occurring neurodevelopmental conditions (e.g., autism) and non-verbal IQ did not correlate with the presence of CAS. Findings indicate that CAS is highly prevalent in children with 16p11.2 deletion with symptoms persisting into adulthood for many. Yet CAS occurs in the context of a broader speech and language profile and other neurobehavioral deficits. Further research will elucidate specific genetic and neural pathways leading to speech and language deficits in individuals with 16p11.2 deletions, resulting in more targeted speech therapies addressing etiological pathways.

Spondylocostal dysostosis in a pregnancy complicated by confined placental mosaicism for tetrasomy 9p

The spondylocostal dysostoses (SCD) are a clinically and genetically heterogeneous group of disorders characterized by defects of vertebral segmentation and rib abnormalities. We report on the diagnosis of two siblings with SCD. Diagnosis was first made in a female infant following a pregnancy that was complicated by early fetal hydrops and a nuchal translucency of 8.2 mm in the first trimester. The clinical picture was complicated by the co‐existent diagnosis of confined placental mosaicism (CPM) for tetrasomy 9p. To our knowledge, this is the first report of CPM for tetrasomy 9p. Postnatally the diagnosis of SCD was made on the basis of radiographic findings comprising multiple anomalies of the cervical and thoracic vertebrae and multiple fused and dysplastic ribs. Radiographic investigation of other family members showed that the infants 4‐year‐old sibling had fusion of four ribs on the right side, indicating a less severe form of SCD. Testing of the genes DLL3, MESP2, and LFNG did not identify a mutation, suggesting that the siblings may have a new molecular subtype of SCD.

ADGRV1 is implicated in myoclonic epilepsy

To investigate the significance of variation in ADGRV1 (also known as GPR98, MASS1, and VLGR1), MEF2C, and other genes at the 5q14.3 chromosomal locus in myoclonic epilepsy.

Corrigendum: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Clara D M van Karnebeek, Luisa Bonafé, Xiao-Yan Wen, Maja Tarailo-Graovac, Sara Balzano, Beryl Royer-Bertrand, Angel Ashikov, Livia Garavelli, Isabella Mammi, Licia Turolla, Catherine Breen, Dian Donnai, Valerie Cormier, Delphine Heron, Gen Nishimura, Shinichi Uchikawa, Belinda Campos-Xavier, Antonio Rossi, Thierry Hennet, Koroboshka Brand-Arzamendi, Jacob Rozmus, Keith Harshman, Brian J Stevenson, Enrico Girardi, Giulio Superti-Furga, Tammie Dewan, Alissa Collingridge, Jessie Halparin, Colin J Ross, Margot I Van Allen, Andrea Rossi, Udo F Engelke, Leo A J Kluijtmans, Ed van der Heeft, Herma Renkema, Arjan de Brouwer, Karin Huijben, Fokje Zijlstra, Thorben Heisse, Thomas Boltje, Wyeth W Wasserman, Carlo Rivolta, Sheila Unger, Dirk J Lefeber, Ron A Wevers & Andrea Superti-Furga Nat. Genet. 48, 777–784 (2016); published online 23 May 2016; corrected after print 6 March 2017

Characterization of speech and language phenotype in children with NRXN1 deletions

Neurexin 1 gene (NRXN1) deletions are associated with several neurodevelopmental disorders. Communication difficulties have been reported, yet no study has examined specific speech and language features of individuals with NRXN1 deletions. Here, we characterized speech and language phenotypes in 21 children (14 families), aged 1.8–17 years, with NRXN1 deletions. Deletions ranged from 74 to 702 kb and consisted mostly of either exons 1–3 or 1–5. Speech sound disorders were frequent (69%), although few were severe. The majority (57%) of children had difficulty with receptive and/or expressive language, although no homogeneous profiles of deficit were seen across semantic, morphological, or grammatical systems. Social language difficulties were seen in over half the sample (53%). All but two individuals with language difficulties also had intellectual disability/developmental delay. Overall, while speech and language difficulties were common, there was substantial heterogeneity in the severity and type of difficulties observed and no striking communication phenotype was seen. Rather, the speech and language deficits are likely part of broader concomitant neurodevelopmental profiles (e.g., intellectual disability, social skill deficits). Nevertheless, given the high rate of affectedness, it is important speech/language development is assessed so interventions can be applied during childhood in a targeted and timely manner.