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 1.7M, 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; 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?

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. 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 GALT OOA – Glaucoma CYP1B1 OOA – Hemophagocytic perforin OOM lymphohistiocytosis – MSUD BCKD OOM

What’s the diagnosis? • 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. 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

www.biochemgenetics.ca/plainpeople