New genetic discoveries are made every day. Over the last two decades researchers have uncovered a large number of genes responsible for genetic diseases, discovered new mechanisms responsible for genetic disorders and developed new technologies allowing us to consider screening and testing for a large number of conditions. These discoveries have brought many challenges for clinical and molecular geneticists: if we identify a change in a gene, is it a mutation that causes the disease or a normal variant? Can we predict disease outcome based on the change in the gene? Can we use new molecular technologies to provide more costly and rapid or more sensitive diagnosis of certain conditions compared to that currently achieved with cytogenetic analysis? What is the outcome of pregnancies found to have abnormal prenatal results on screening or testing? As a clinical and molecular geneticist facing a number of these problems in daily practice, my research aims to answer these questions and directly impact patient care.

Outcome analysis of pregnancies screened positive for Smith Lemli Opitz
SLOS is an autosomal recessive disorder characterized by growth retardation, developmental delay and minor / major anomalies. It is caused by a deficiency of 7-dehydrocholesterol reductase and is associated prenatally with a low maternal uE3. Screening for SLOS is part of the prenatal MSS offered to all pregnant women. As SLOS is a very rare disorder, it has become apparent that screening positive for SLOS identifies pregnancies at risk of numerous other conditions and rarely is the cause of the abnormal screen SLOS. Our study aims at determining the prenatal and postnatal outcome of all pregnancies screening positive for SLOS so that the significance of a positive screen is better understood and patients counselled and managed accordingly.

Genotype-Phenotype correlation in the GJB2 (Connexin 26) gene
Mutations in the GJB2 gene are a major cause of autosomal recessive congenital deafness. As numerous centers offer mutation analysis of this gene in patients with deafness, sequence variants are identified and their pathogenetic nature may be questioned. V37I is one such variant said to be pathogenic in some publications and classified as a polymorphism in others. Given the high frequency of V37I in individuals of Chinese descent, our study aims at determining the significance of this sequence variation in patients with SNHL. We hypothesize that V37I is common in individuals of Chinese descent but rare in Caucasians, is pathogenic and associated with mild to moderate SNHL.

Genomic tools in the study of mental retardation
The use of conventional cytogenetic techniques to study patients with mental retardation fails to identify an abnormality in the majority of these patients. FISH analysis uncovers a microdeletion in a subset of patients with well-defined clinical phenotypes (e.g. microdeletion 22, Williams syndrome). Microarray Comparative Genomic Hybridization has the potential to detect small microdeletion and microduplications throughout the genome and is therefore potentially a powerful tool to uncover the cause of the mental retardation in a significant proportion of patients. The aim of our study is to validate the use of this tool in 100 patients with developmental delay/mental retardation by screening the patients using mA-CGH and validating the findings using molecular cytogenetics.

Bruyere H, Wilson RD , Langlois S. Risk of mosaicism and uniparental disomy associated with the prenatal diagnosis of a non-homologous Robertsonian translocation carrier. Fetal Diagnosis and Therapy 19:399-403, 2004.

Shalev SA, Clarke LA, Koehn D, Langlois S, Zackai EH, Hall JG, Mcdonald McGinn DM. Long term follow-up of three individuals with Kabuki Syndrome. American Journal of Medical Genetics 125A: 191-200, 2004.

Beever, CL, Penaherrera MS, Langlois S, Robinson WR. X chromosome inactivation patterns in Russell-Silver syndrome patients and their mothers. American Journal of Medical Genetics 123A: 231-235, 2003.

Bruyere H, Rajcan-Separovic E, Doyle J, Pantzar T, Langlois S. Familial cryptic translocation (2;17) ascertained through recurrent spontaneous abortions. American Journal of Medical Genetics 123A:285-289, 2003.

McFadden DE , Jiang R, Langlois S, Robinson WP. Dispermy – origin of diandric triploidy: brief communication. Human Reproduction, 17:3037-3038, 2002.

Mattman A, Huntsman D, Lockitch G, Langlois S, Buskard N, Ralston D, Butterfield Y, Rodrigues P, Jones S, Porto G, Marra M, De Sousa M, Vatcher G. Transferrin receptor 2 (TtR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TtR2 mutation. Blood, 100(3):1075-7, 2002.

Robinson WP, McFadden DE, Barrett IJ, Kuchinka B, Penaherrera MS, Bruyere H, Best RG, Pedreira DAL, Langlois S, Kalousek DK. Origin of amnion and implications for evaluation of the fetal genotype in cases of mosaicism. Prenatal Diagnosis, 22:1076-1085, 2002.

Goudeau B, Dagvadorj A, Rodrigues-Lima F, Dedellec P, Casteras-Simon M, Perret E, Langlois S, Goldfarb L, and Vicart P. Structural and functional analysis of a new desmin variant causing desmin-related myopathy. Human mutation, 18:388-396, 2001.

Kuchinka BD, Barrett IJ, Moya G, Sanchez JM, Langlois S et al. Two cases of confined placental mosaicism for chromosome 4, including one with maternal uniparental disomy. Prenatal Diagnosis, 21 (1): 36-39, 2001.

UBC Faculty of Medicine Killam University Teaching Prize – 2003

Technologists:

Darko Curman

Kristie Garbutt

Nasim Ali Akbarli