Glycogen Storage Disease Type IV/ Adult Polyglucosan Body Disease Carrier Screening Ruth Kornreich, Ph.D.

Jewish genetic diseases 1970’s & 1980’s: Ashkenazi Jewish genetic diseases were recognized as a major problem to be addressed 2000: Dr. Michael Kaback, “United States and Canada, the incidence of TSD in the Jewish population had declined by more than 90%” Since the creation of the AJP and with the efforts of such organizations as Dor Yesharim and JGDC the incidence of genetic diseases in the Ashkenazi community has dramatically decreased.

RECOMMENDED ASHKENAZI JEWISH (AJ) CARRIER SCREENING Disease Recommendation AJ Carrier Frequency Pan-ethnic Diseases ACMG ACOG Cystic fibrosis (CF)  1 in 23 Fragile X syndrome (FX) 1 in 134 Spinal muscular atrophy (SMA) 1 in 41 AJ Diseases Bloom syndrome (BS) ü    1 in 134 Canavan disease (CD)  1 in 55 Familial dysautonomia (FD)  1 in 31 Fanconi anemia group C (FA)  1 in 100 Gaucher disease (GD)  1 in 15 Mucolipidosis IV (MLIV)  1 in 89 Niemann-Pick disease type A (NPD-A)  1 in 115 Tay-Sachs disease (TSD)  1 in 27 Current guidelines recommend that individuals with Ashkenazi Jewish ancestry should be offered prenatal or preconceptional testing for at least 11 well-known diseases. 3 of them, cystic fibrosis, fragile X syndrome and spinal muscular atrophy, are common disorders prevalent in both Ashkenazi Jewish population and non-AJ Caucasians. The other 8 diseases are predominantly presented in AJ patients, with known AJ carrier frequency from highest 1 in 15 for Gaucher disease to about 1 in 134 for Bloom syndrome.

ADDITIONAL SCREENING OPTIONS Additional AJ Diseases Additional AJ Panel Expanded Pan-Ethnic Panel AJ Carrier Frequency Familial hyperinsulinism  1 in 68 Glycogen storage disease Ia 1 in 64 Joubert syndrome 2 1 in 110 Lipoamide dehydrogenase deficiency 1 in 107 Maple syrup urine disease Ib 1 in 97 Nemaline myopathy 1 in 168 Usher syndrome type IF 1 in 147 Usher syndrome type III 1 in 120 Walker-Warburg syndrome 1 in 90 Abetalipoproteinemia 1 in 131 Galactosemia Hermansky-Pudlak syndrome 1 in 235 LDLR-Hypercholesterolemia 1 in 67 Smith-Lemli-Opitz syndrome 1 in 100 Tyrosinemia type 1 Wilson disease Zellweger syndrome Carrier screening for extra diseases is also offered for Ashkenazi Jewish individuals from a number of laboratories, although these additional diseases have not been formally recommended by guidelines. Some of these disorders are included in additional AJ panels because patients of these diseases are more often seen in Ashkenazi Jewish population. While testing for other common diseases is also available for AJ individuals from several expanded pan-ethnic carrier screening panels because they are also prevalent in non-AJ populations. As our knowledge of Mendelian disorders has rapidly expanded due to recent technological advances, more and more disease-associated founder mutations have been reported in Ashkenazi Jewish patients. However, lack of sufficient population study for these diseases makes it difficult to evaluate disease carrier prevalence and estimate of residual risk in Ashkenazi Jewish population.

Expanded Carrier Screening: Standard of Care

Expanded Carrier Screening: Standard of Care ACMG Five criteria should be met for a disorder to be included on a panel: Most at risk patients would consider having prenatal diagnosis to facilitate reproductive decision making Patients must provide consent to screen for adult-onset disorders (especially where there may be implications for the individual or their family members) For each condition, the causative genes, mutations, and mutation frequencies should be known in the population being tested so that residual risk for those that test negative can be correctly assessed Validated clinical association between the mutations detected and the severity of the disorder Compliance with the ACMG Standards and Guidelines for Clinical Genetics Laboratories

Genotyping versus Sequencing Technologies used for Carrier Screening Historically carrier screening was limited to genotyping. Relatively Cheap Relatively Fast Straightforward “carrier” or “non-carrier” for predefined set of mutations Historically full gene sequencing was reserved for diagnostic purposes. Expensive Time Consuming Could reveal confusing results

Expanded Carrier Screening in Reproductive Medicine A Joint Statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine INTERPRETATION OF MOLECULAR FINDINGS The genes and variants included should have a well-understood relationship with a phenotype. Phenotype–genotype correlation should at a minimum include multiple families that provide a minimum level of unbiased ascertainment. Laboratories should be able to provide information about the phenotype for any conditions included on a panel. When the carrier frequency and detection rate are both known, residual risk estimation should be provided in laboratory reports. Where this information is not available or reliable, the limitations of interpretation of negative screening should be clearly communicated in laboratory reports. Because all individuals have numerous variants within their genes, restricting the variants that are included in screening to those with the highest likelihood of being pathogenic will decrease the number of people who require follow-up. Variants of uncertain significance detected by sequencing should not be reported The laboratory performing screening should report all variants that are pathogenic or likely pathogenic.

MGTL carrier screening expansion philosophy Disease selection criteria Early-onset, severe Childhood or early adult onset and progressive Early detection for prevention of catastrophic events or for better lifetime disease management

Ashkenazi Jewish carrier screening (expansion #1): 18 new diseases

Ashkenazi Jewish Carrier Screening (expansion to sequencing #2): 20 new diseases Choreoacanthocytosis VPS13A Deafness, Autosomal Recessive 77 LOXHD1 (1/180) Enhanced S-Cone Syndrome NR2E3 Factor XI Deficiency F11 (1/11) Familial Hypercholesterolemia LDLR (1/69) Glycogen Storage Disease, Type IV / Adult Polyglucosan Body Disease GBE1 (1/68) Glycogen Storage Disease, Type VII PFKM (1/250) Hermansky-Pudlak Syndrome, Type 3 HPS3 (1/235) Mitochondrial Complex I Deficiency NDUFAF5 (1/290) Non-Syndromic Hearing Loss (GJB2-Related) GJB2 (1/21) Osteopetrosis 1 TCIRG1 (1/350) Pontocerebellar Hypoplasia, Type 1A VRK1 (1/225) Primary Ciliary Dyskinesia DNAH5 (1/174) Primary Ciliary Dyskinesia DNAI1 (1/352) Primary Ciliary Dyskinesia DNAI2 (1/200) Primary Hyperoxaluria, Type 3 HOGA1 17. Familial Mediterranean Fever MEFV (1/13) 18. Glycogen Storage Disease, Type II GAA (1/58) 19. Phenylalanine Hydroxylase Deficiency PAH (1/225) 20. Retinitis Pigmentosa 28 FAM161A (1/214) 8 out of 10 Ashkenazi Jewish individuals tested for 58 disorders will screen positive

Carrier Frequency of GBE1 Pathogenic and Likely Pathogenic Variants Obtained During Screening of 2775 Ashkenazi Jewish Individuals Variant n p.Y329S 38 IVS15+5289delins 16 p.Y329C 2 p.Y535C 1 p.G299X 1 Overall carrier frequency of 1 in 48 (58/2775)

Carrier Frequency of GBE1 Pathogenic and Likely Pathogenic Variants Obtained During Screening of 21319 Individuals Variant n p.Y329S 63 IVS15+5289delins 29 p.Y329C 53 c.691+2T>C 32 15 Other variants (n=1-3) 20 Overall carrier frequency of 1 in 108 (197/21319)