DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
EDITORIAL
Studying rare genetic disorders in child neurology – the need for an international network of collaboration With the advent of high-throughput DNA sequencing, genetic causes of monogenic (Mendelian) disorders are being identified at an unprecedented rate. However, there are still thousands of monogenic disorders that remain to be identified.1 Since the developing nervous system is frequently affected by monogenic disorders, the role of child neurologists in this area of research is particularly important. As the genetic basis for many common genetic disorders has already been solved, current gene identification efforts are focusing more on extremely rare disorders. It is often necessary to find multiple, independent mutant alleles in the same gene to prove the association between a gene and a disorder. A major challenge is to find multiple independent families with a rare disorder in one geographical region. Therefore, the development of international collaborative networks is essential when studying rare disorders. The International Child Neurology Association (ICNA) offers such an opportunity through its Research Committee. The following is an example of how ICNA can facilitate such endeavours. Recently, we reported biallelic deletions of the GRID2 (glutamate receptor, ionotropic, delta 2) gene as the cause of a neurological disorder characterized by cerebellar atrophy and eye movement abnormalities, most notably involuntary tonic upgaze.2 In this research effort, one pedigree was enrolled in Jordan and the other in the USA. This international collaboration proved the key to success, as identification of independent GRID2 deletions in these unrelated families strongly supported the pathogenicity of these mutations. We also realized that involuntary tonic upgaze noted in the affected individuals resembled that in paroxysmal tonic upgaze (PTU), characterized by episodes of variably sustained conjugate upward deviation of the eyes.3 Although PTU is probably heterogeneous in its etiology, it is reasonable to speculate that some cases could be due to GRID2 mutations. Since PTU is also rare (with
approximately 50 cases reported between 1988 and 2002), affected individuals need to be ascertained worldwide. Such effort, as well as research collaborations for many other rare disorders, will be facilitated by an international network of research collaboration among child neurologists as offered by ICNA. Another example that highlights the importance of international collaboration through ICNA in rare genetic disorders is the identification of mutations in the JAM3 gene. Mochida et al. ascertained a pedigree from the United Arab Emirates consisting of five children affected with hemorrhagic destruction of the brain, subependymal calcification, and cataracts. They identified a homozygous mutation of the JAM3 (junctional adhesion molecule 3) gene, which encodes a protein component of tight junctions.4 At the time of that study, no other individuals with similar clinical features had been reported in the literature and, therefore, only one mutant allele could be identified. After the publication of the paper, however, clinicians from different parts of the world, including Turkey, Australia, and Spain, came forward with similar cases and additional JAM3 mutations were quickly identified.5 Currently there is no worldwide platform for pediatric neurologists to share information about patients with rare disorders and establish research collaborations. As the largest international community of child neurologists, ICNA is optimally poised to facilitate such an initiative. ICNA welcomes proposals from researchers who can benefit from this service. These proposals will then be freely available on the ICNA website (http://www.icnapedia.org).
GANESHWARAN H MOCHIDA1 | HARRY CHUGANI2 1 Genetics and Genomics, Boston Children’s Hospital, Boston, MA; 2 Pediatric Neurology, Wayne State University School of Medicine, Detroit, MI, USA. doi: 10.1111/dmcn.12444
REFERENCES 1. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequenc-
4. Mochida GH, Ganesh VS, Felie JM, et al. A homozygous
ing as a tool for Mendelian disease gene discovery. Nat
mutation in the tight-junction protein JAM3 causes
fication, and congenital cataracts. Hum Mutat 2013; 34:
Rev Genet 2011; 12: 745–55.
hemorrhagic destruction of the brain, subependymal
498–505.
2. Hills LB, Masri A, Konno K, et al. Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. Neurology 2013; 81: 1378–86. 3. Ouvrier R, Billson F. Paroxysmal tonic upgaze of childhood–a review. Brain Dev 2005; 27: 185–8.
412
hemorrhagic destruction of the brain, subependymal calci-
calcification, and congenital cataracts. Am J Hum Genet 2010; 87: 882–9. 5. Akawi NA, Canpolat FE, White SM, et al. Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations
underlying
the
autosomal
recessive
© 2014 Mac Keith Press
EDITORIAL
Studying rare genetic disorders in child neurology – the need for an international network of collaboration With the advent of high-throughput DNA sequencing, genetic causes of monogenic (Mendelian) disorders are being identified at an unprecedented rate. However, there are still thousands of monogenic disorders that remain to be identified.1 Since the developing nervous system is frequently affected by monogenic disorders, the role of child neurologists in this area of research is particularly important. As the genetic basis for many common genetic disorders has already been solved, current gene identification efforts are focusing more on extremely rare disorders. It is often necessary to find multiple, independent mutant alleles in the same gene to prove the association between a gene and a disorder. A major challenge is to find multiple independent families with a rare disorder in one geographical region. Therefore, the development of international collaborative networks is essential when studying rare disorders. The International Child Neurology Association (ICNA) offers such an opportunity through its Research Committee. The following is an example of how ICNA can facilitate such endeavours. Recently, we reported biallelic deletions of the GRID2 (glutamate receptor, ionotropic, delta 2) gene as the cause of a neurological disorder characterized by cerebellar atrophy and eye movement abnormalities, most notably involuntary tonic upgaze.2 In this research effort, one pedigree was enrolled in Jordan and the other in the USA. This international collaboration proved the key to success, as identification of independent GRID2 deletions in these unrelated families strongly supported the pathogenicity of these mutations. We also realized that involuntary tonic upgaze noted in the affected individuals resembled that in paroxysmal tonic upgaze (PTU), characterized by episodes of variably sustained conjugate upward deviation of the eyes.3 Although PTU is probably heterogeneous in its etiology, it is reasonable to speculate that some cases could be due to GRID2 mutations. Since PTU is also rare (with
approximately 50 cases reported between 1988 and 2002), affected individuals need to be ascertained worldwide. Such effort, as well as research collaborations for many other rare disorders, will be facilitated by an international network of research collaboration among child neurologists as offered by ICNA. Another example that highlights the importance of international collaboration through ICNA in rare genetic disorders is the identification of mutations in the JAM3 gene. Mochida et al. ascertained a pedigree from the United Arab Emirates consisting of five children affected with hemorrhagic destruction of the brain, subependymal calcification, and cataracts. They identified a homozygous mutation of the JAM3 (junctional adhesion molecule 3) gene, which encodes a protein component of tight junctions.4 At the time of that study, no other individuals with similar clinical features had been reported in the literature and, therefore, only one mutant allele could be identified. After the publication of the paper, however, clinicians from different parts of the world, including Turkey, Australia, and Spain, came forward with similar cases and additional JAM3 mutations were quickly identified.5 Currently there is no worldwide platform for pediatric neurologists to share information about patients with rare disorders and establish research collaborations. As the largest international community of child neurologists, ICNA is optimally poised to facilitate such an initiative. ICNA welcomes proposals from researchers who can benefit from this service. These proposals will then be freely available on the ICNA website (http://www.icnapedia.org).
GANESHWARAN H MOCHIDA1 | HARRY CHUGANI2 1 Genetics and Genomics, Boston Children’s Hospital, Boston, MA; 2 Pediatric Neurology, Wayne State University School of Medicine, Detroit, MI, USA. doi: 10.1111/dmcn.12444
REFERENCES 1. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequenc-
4. Mochida GH, Ganesh VS, Felie JM, et al. A homozygous
ing as a tool for Mendelian disease gene discovery. Nat
mutation in the tight-junction protein JAM3 causes
fication, and congenital cataracts. Hum Mutat 2013; 34:
Rev Genet 2011; 12: 745–55.
hemorrhagic destruction of the brain, subependymal
498–505.
2. Hills LB, Masri A, Konno K, et al. Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. Neurology 2013; 81: 1378–86. 3. Ouvrier R, Billson F. Paroxysmal tonic upgaze of childhood–a review. Brain Dev 2005; 27: 185–8.
412
hemorrhagic destruction of the brain, subependymal calci-
calcification, and congenital cataracts. Am J Hum Genet 2010; 87: 882–9. 5. Akawi NA, Canpolat FE, White SM, et al. Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations
underlying
the
autosomal
recessive
© 2014 Mac Keith Press
