HARS and other genetic disorders in Southwestern …

1 HARS and other genetic disorders in Southwestern ontario , canada Victoria Mok Siu Tony Rupar Medical Genetics Program of Southwestern ontario London, ontario Provide general, pediatric, cancer, and prenatal testing Population of , of which ~12,000 are Old Order Largest Anabaptist group is Low German-speaking Mennonite Who provides care to the Plain Population in ontario ? Geneticists and Biochemical Lab Director Public health unit and nurses Midwives Community physicians and pediatricians Nurse practitioner Outreach clinics carrier screening, dental, optometry Specialists at London Health Sciences Centre Anabaptist groups in ontario From Europe Amish Old Order Mennonite Low German speaking Mennonite From the USA Case 1: HARS (histidyl t-RNA synthetase) Original case presented at 1 year Febrile, encephalopathic Loss of hearing and vision Causative gene identified by Puffenberger et al (PLoS One 2012.)

2 7:e28936) Natural history of HARS (7 families, 12 affected children) Initially well Some late to walk Develop hearing loss -> cochlear implant Episodes of mild respiratory illlness, fever, visual hallucinations, high CK, may deteriorate rapidly and lead to sudden death (infancy, childhood) CXR: lung infiltrates (ARDS) MRI: posterior white matter loss, reversible Autopsy: hyaline membranes, pleural effusions, normal heart Population data for HARS Y454S mutation in ontario OOA Haplotype analysis using 4 flanking STRs indicates mutation is on multiple haplotypes and has been present in the population for many generations. How does this affect protein synthesis? Are proteins high in histidine affected disproportionately? Would supplementation with histidine overcome the defect? Causative gene is histidyl t-RNA synthetase (HARS) In the rheumatology world, patients with autoantibodies against histidyl t-RNA synthetase develop myopathy with high creatinine kinase levels, fever, and pulmonary infiltrates A human knockdown model for HARS deficiency?

3 Questions Which comes first, the fever or an infection? What is the precipitating event? Lethal disorder at birth holoprosencephaly, cleft lip and palate, absent pituitary, Limb defects: polydactyly, short limbs Case 2: Endocrine-cerebro-osteodysplasia (ECO) syndrome ECO syndrome Causative gene is ICK (intestinal cell kinase), described by Lahiry et al. (Am J Hum Genet 2009; 84: 134-47) Recently identified as a ciliopathy by Moon et al. (Proc Natl Acad Sci U S A 2014; 111: 8541-6) and Chaya (EMBO J. 2014; 33: 1227-42) ICK knockout mouse recapitulates human malformations Shortened, S-shaped anterior limbs Polydactyly Hydrocephalus Cultured cells have fewer and shorter cilia Case 3. Syndromic sodium diarrhea Polyhydramnios in-utero Profuse watery diarrhea, metabolic acidosis Intestinal atresia/choanal atresia/preauricular pits Treatment: TPN for life Why the malformations? Maybe not true malformations, but disruption of normal development due to altered surface fluid layer in intestinal lumen Compare with bilateral absence of vas deferens or intestinal atresia in CF Case 4.

4 Gastric intrinsic factor deficiency In the Old Order Mennonites: Present in the first year of life Responds beautifully to oral B12 treatment Causative gene (GIF) identified by Ferrand et al. (2014, in press) Since 2004: targeted newborn DNA screening for treatable disorders High Carrier rates: cystinosis (CTNS) 1:5 cystic fibrosis (CFTR) 1:7 galactosemia (GALT) 1:7 glaucoma (CYP1B1) 1:11 Strong support of midwives 90% uptake Have added HARS No longer testing for CF or galactosemia (included in ontario Newborn Screening Program) Since 1968 PKU, later TSH ~2004 - newborn hearing screening (high rate of congenital deafness in OOM) 2006 expanded NBS 29 disorders Inclusion of CF3905insT (OOA) 2013 SCID (ZAP70 kinase, ADA deficiency, CD3delta in Low German Speaking Mennonites) Family members began requesting carrier testing for adults Clinics held for testing of large groups Galactosemia G A LT OOA Glaucoma CYP1B1 OOA Hemophagocytic perforin OOM lymphohistiocytosis MSUD BCKD OOM What s the diagnosis?

5 NICU calls: We have a premature baby with cloudy corneas and choanal atresia Old Order Amish: dual diagnosis Congenital glaucoma CYP1B1 Sodium diarrhea SPINT2 The joys of working with the Amish Taking time to ponder The opportunity to look beyond my office window Unusual problems Practical solutions Hospital fees canada s healthcare system provides healthcare to all citizens Plain people pay for healthcare with their taxes but some groups do not wish to be beholden to the government, therefore wish to pay additionally for their healthcare and do not carry health insurance cards Thanks to the efforts and example of other clinics working with Plain people, we have been able to persuade our hospital administration to lower the inpatient hospital fees by 50%. Old Order Networking meeting Stratford ontario Jane Leach, public health nurse extraordinaire Last year 300 in attendance Dr.

6 Holmes Morton will be the keynote speaker on October 10, 2014 We can t remember it all! We don t see the same disorders We need to share our knowledge