Our experience in PGD for single gene disorders

A total of 334 couples underwent 561 PGD cycles for 45 different indications (Table I).The mean maternal age was 31.8 4.3 years, ranging from 21 to 44.

The single gene defects investigated included autosomal dominant (34 cycles; 22 couples), autosomal recessive (303 cycles; 191 couples) and X linked disorders (27 cycles; 15 couples). A total of 197 cycles, for 106 couples, were also performed for HLA matching.

Myotonic dystrophy was the most frequent autosomal dominant disease tested (n = 9). β-Thalassemia was the most frequent autosomal recessive disorder (n = 217), followed by cystic fibrosis (n = 40), and Spinal Muscular Atrophy (n = 15). Haemophilia A (n = 6) and Duchenne muscular dystrophy (n = 5%) were the most frequent X-linked disorders investigated.

A total of 4663 embryos were analysed. PCR amplification was successful in 6057 out of 6664 blastomeres (91.0%). Amplification failed for all the markers/loci tested in 607 blastomeres. The efficiency of amplification for the individual genetic conditions ranged from 80.0% to 100%, with an overall amplification rate of 92.4%. The ADO rates varied between the different loci/markers investigated, ranging from 0,0% to 12,9%, with an average ADO rate of 7.5%.

Overall, 4269 (91.6%) embryos were successfully genotyped in the 561 clinical cycles.

Following transfer of 758 embryos, 141 women had positive hCG levels (35.7% pregnancy rate per embryo transfer), 116 of which were confirmed with fetal sacs and heart beat. 25 pregnancies spontaneously miscarried within the first trimester and two ectopic pregnancies were terminated. 38 pregnancies are still ongoing, whereas the others 69 went to term without complications, resulting in the birth of healthy babies.


Table I

Disease

Gene

N. Cycles

N. Couples

N. of clinical pregnancies

N. of pregnancies still ongoing

N. of pregnancies delivered

Autosomal Dominant   34 22 8 3 5
Charcot Marie Tooth type 1A PMP22 1 1 1 1 0
Congenital fibrosis of extraocular muscles KIF21A 2 1 0 0 0
Hand-Foot-Uterus syndrome / Synopolydactlyly HOXD13-
HOXA13
2 1 0 0 1
Holt-Oram Syndrome TBX5 1 1 1 0 1
Huntington HD 3 3 2 1 1
Li-Fraumeni Syndrome p53 2 1 0 0 0
Myotonic dystrophy DMPK 9 5 0 0 0
Neurofibromatosis type 1 NF1 4 3 1 1 0
Retinoblastoma RB1 4 2 0 0 0
Tuberossclerosis 1 TSC1 1 1 1 0 1
Spastic Paraplegia type3 SPG3A 1 1 1 0 1
Torsion dystonia, early onset DYT1 3 1 1 0 2
Von Hippel-Lindau syndrome VHL 1 1 0 0 0
             
Autosomal Recessive   240 156 55 19 36
3-Hydroxyisobutyryl-CoA hydrolase deficiency HIBCH 1 1 0 0 0
Cystic Fibrosis CFTR 40 30 9 1 7
Congenital adrenal hyperplasia CYP21A2 3 3 1 1 0
Factor VII deficiency F7 1 1 1 0 0
Familial Mediterranean Fever MEVF 2 1 0 0 0
Gangliosidosis GLB1 2 1      
Homocystinuria MTHFR 1 1 1 1 0
Hypomagnesemia CLDN16 1 1 0 0 0
Limb-girdle muscular dystrophy type 2C SGCG 1 1 0 0 0
Mevalonic aciduria MVK 1 1 0 0 0
Mucopolysaccharidosis Type IIIA - Sanfilippo sindrome A SGSH 5 1 1 1 0
Mucopolysaccharidosis type IIIB - Sanfilippo syndrome B NAGLU 1 1 1 1 0
Mucopolysaccharidosis Type VI - Maroteaux-Lamy Syndrome ARSB 2 1 1 0 1
Neuronal ceroid lipofuscinosis 1 - Batten's disease PPT1 1 1 1 0 1
Niemann-Pick disease SMPD1 1 1 1 1 0
Tay Sachs HEXA 1 1 0 0 0
Thalassemia - β HBB 217 127 31 9 21
Sickle cell anemia HBB 7 4 2 1 1
Spinal Muscular Atrophy SMN 15 13 5 3 3
             
X-linked   27 15 11 2 7
Adrenoleukodystrophy ABCD1 3 2 1 1 0
Alpha-Thalassemia mental retardation syndrome ATRX 1 1 0 0 0
Charcot Marie Tooth type X CMTX 3 1 3 0 1
Chronic granulomatous disease CYBB 1 1 1 0 2
Duchenne muscular dystrophy DMD 5 2 1 0 1
Fragile - X FRAXA 2 1 0 0 0
Glucose-6-phosphate dehydrogenase deficiency G6PD 1 1 0 0 0
Haemophilia A F8 6 3 3 1 1
Haemophilia B F9 3 1 1 0 1
Lesch-Nyhan syndrome HPRT 1 1 0 0 0
Wiskott-Aldrich Syndrome WAS 1 1 1 0 1
             
Specific traits   197 106 42 14 20
SGD + HLA Matching Gene + HLA 159 88 34 11 18
HLA Matching only HLA 38 18 8 3 2
TOTAL 561 334   116 38 69




Table II

Disease

 
HOLT-ORAM syndrome 1 1 6 12 11 91,7 6 100,0
Charcot Marie Tooth type 1A (CMT1A) 1 1 7 14 13 92,9 7 100,0
congenital fibrosis of extraocular muscles 2 1 21 21 21 100,0 21 100,0
Myotonic dystrophy (DM) 9 5 41 63 56 88,9 38 92,7
Torsion dystonia, early onset (EOTD) 3 1 26 52 48 92,3 26 100,0
HAND-FOOT-UTERUS SYNDROME/SYNPOLYDACTYLY 2 1 18 11 10 90,9 15 83,3
Huntington 3 3 22 31 30 96,8 21 95,5
Li-Fraumeni (P53) 2 1 12 24 24 100,0 12 100,0
Neurofibromatosi type 1 4 3 19 33 28 84,8 14 73,7
Retinoblastoma 4 2 28 56 53 94,6 28 100,0
Tuberosclerosis 1 1 4 8 8 100,0 4 100,0
Spastic paraplegia type 3 1 1 12 22 21 95,5 11 91,7
von Hippel-Lindau sindrome 1 1 2 4 4 100,0 2 100,0
Total Auttosomal dominant 34 22 218 351 327 93.2 205 1237
                 
β-Thalassemia 217 127 1889 2687 2421 90,1 1674 88,6
Cystic Fibrosis 40 30 243 371 336 90,6 227 93,4
Batten's disease 1 1 6 6 5 83,3 5 83,3
Congenital adrenal hyperplasia (CAH) 3 3 32 33 27 81,8 26 81,3
Factor VII deficiency 1 1 18 18 18 100,0 18 100,0
Familial Mediterranean Fever (FMF) 2 1 4 8 8 100,0 4 100,0
GANGLIOSIDOSIS 2 1 6 11 10 90,9 6 100,0
3-Hydroxyisobutyryl-CoA hydrolase def 1 1 10 10 10 100,0 10 100,0
hypomagnesemia 1 1 13 13 8 61,5 8 61,5
Homocystinuria 1 1 2 4 4 100,0 2 100,0
Mevalonic aciduria 1 1 6 6 5 83,3 5 83,3
Mucopolysaccharidosis Type IIIA
- Sanfilippo sindrome A (MPS3A)
5 1 46 68 60 88,2 40 87,0
Mucopolysaccharidosis Type IIIB
- Sanfilippo sindrome B (MPS3B)
1 1 4 8 8 100,0 4 100,0
Mucopolysaccharidosis Type VI (MPS VI)
- Maroteaux-Lamy Syndrome
2 1 10 16 12 75,0 7 70,0
Limbe-gridle Muscular dystrophy 1 1 5 9 8 88,9 4 80,0
Niemann-Pick disease 1 1 0 15 14 93,3 14 0
Tay Sacs 1 1 10 20 20 100,0 10 100,0
Sickle cell 7 4 45 80 75 93,8 41 91,1
Spinal Muscular Atrophy (SMA) 15 13 98 149 127 85,2 86 87,8
Total Auttosomal recessive 303 191 2447 3532 3176 90.0 2191 0
                 
Adrenoleukodystrophy 3 2 13 19 19 100,0 13 100,0
Lesch-Nyhan syndrome 1 1 2 4 4 100,0 2 100,0
Charcot Marie Tooth type X (CMTX) 3 1 29 35 33 94,3 27 93,1
Chronic granulomatous disease 1 1 15 15 15 100,0 15 100,0
Duchenne muscular dystrophy 5 2 24 48 42 87,5 24 100,0
Glucose-6-phosphate dehydrogenase deficiency 1 1 15 30 28 93,3 14 93,3
Fragile-X 2 1 18 18 14 77,8 14 77,8
Haemophilia A 6 3 25 46 41 89,1 24 96,0
Haemophilia B 3 1 20 40 36 90,0 20 100,0
Lesch-Nyhan (HPRT) 1 1 7 14 12 85,7 7 100,0
Wiskott-Aldrich Syndrome 1 1 13 20 18 90,0 9 69,2
Total X-linked 27 15 181 289 262 90.7 169 1029
                 
SGD+HLA matching 159 88 1488 2077 1914 92,2 1402 94,2
HLA Matching only 38 18 329 415 378 91,1 302 91,8
Total 561 334 4663 6664 6057 91.0 4269 91,6



Table III


 

Disease s
HOLT-ORAM syndrome 1 1 2 1 100,0 0 1 0 0 100,0 100,0 1
Charcot Marie Tooth type 1A (CMT1A) 1 1 1 1 100,0 0 1 0 1 100,0 100,0 0
congenital fibrosis of extraocular muscles 2 1 4 0 0,0 0 0 0 0 0,0 0,0 0
Myotonic dystrophy (DM) 9 5 10 1 16,7 1 0 0 0 0,0 0,0 0
Torsion dystonia, early onset (EOTD) 3 1 8 1 33,3 0 1 0 0 33,3 100,0 2
HAND-FOOT-UTERUS SYNDROME/SYNPOLYDACTYLY 2 1 0 0 0 0 0 0 0 0 0,0 0
Huntington 3 3 8 2 66,7 0 2 0 1 66,7 66,7 1
Li-Fraumeni (P53) 2 1 5 0 0,0 0 0 0 0 0,0 0,0 0
Neurofibromatosi type 1 4 3 3 2 66,7 1 1 0 1 33,3 33,3 0
Retinoblastoma 4 2 9 1 25,0 1 0 0 0 0,0 0,0 0
Tuberosclerosis 1 1 1 1 100,0 0 1 0 0 100,0 100,0 1
Spastic paraplegia type 3 1 1 1 1 100,0 0 1 0 0 100,0 100,0 1
von Hippel-Lindau sindrome 1 1 1 0 0,0 0 0 0 0 0,0 0,0 0
Total Auttosomal dominant 34 22 53 11 0 3 8 0 3 0 600 6
                         
β-Thalassemia 217 127 265 40 30,5 9 31 12 9 23,7 24,4 21
Cystic Fibrosis 40 30 88 9 23,7 0 9 1 1 23,7 30,0 7
Batten's disease 1 1 1 1 100,0 0 1 0 0 100,0 100,0 1
Congenital adrenal hyperplasia (CAH) 3 3 7 1 33,3 0 1 0 1 33,3 33,3 0
Factor VII deficiency 1 1 3 1 100,0 0 1 0 0 100,0 100,0 2
Familial Mediterranean Fever (FMF) 2 1 3 1 100,0 1 0 0 0 0,0 0,0 0
GANGLIOSIDOSIS 2 1 3 0 0,0 0 0 0 0 0,0 0,0 0
3-Hydroxyisobutyryl-CoA hydrolase def 1 1 3 0 0,0 0 0 0 0 0,0 0,0 0
hypomagnesemia 1 1 2 0 0,0 0 0 0 0 0,0 0,0 0
Homocystinuria 1 1 1 1 100,0 0 1 0 1 100,0 100,0 0
Mevalonic aciduria 1 1 2 0 0,0 0 0 0 0 0,0 0,0 0
Mucopolysaccharidosis Type IIIA - Sanfilippo sindrome A (MPS3A) 5 1 15 3 60,0 2 1 0 1 20,0 100,0 0
Mucopolysaccharidosis Type IIIB - Sanfilippo sindrome B (MPS3B) 1 1 3 1 100,0 0 1 0 1 100,0 100,0 0
Mucopolysaccharidosis Type VI (MPS VI) - Maroteaux-Lamy Syndrome 2 1 4 1 50,0 0 1 0 0 50,0 100,0 1
Limbe-gridle Muscular dystrophy 1 1 3 0 0,0 0 0 0 0 0,0 0,0 0
Niemann-Pick disease 1 1 2 1 100,0 0 1 0 1 100,0 100,0 0
Tay Sacs 1 1 3 0 0,0 0 0 0 0 0,0 0,0 0
Sickle cell 7 4 14 3 42,9 1 2 0 1 28,6 50,0 1
Spinal Muscular Atrophy (SMA) 15 13 28 5 38,5 0 5 0 3 38,5 38,5 3
Total Auttosomal recessive 303 191 450 68 879 13 55 13 19 718 876 36
                         
Adrenoleukodystrophy 3 2 2 1 50,0 0 1 0 1 50,0 50,0 0
Lesch-Nyhan syndrome 1 1 0 0 0 0 0 0 0 0 0,0 0
Charcot Marie Tooth type X (CMTX) 3 1 7 3 100,0 0 3 2 0 100,0 300,0 1
Chronic granulomatous disease 1 1 2 1 100,0 0 1 0 0 100,0 100,0 2
Duchenne muscular dystrophy 5 2 8 1 25,0 0 1 0 0 25,0 50,0 1
Glucose-6-phosphate dehydrogenase deficiency 1 1 3 0 0,0 0 0 0 0 0,0 0,0 0
Fragile-X 2 1 1 1 100,0 1 0 0 0 0,0 0,0 0
Haemophilia A 6 3 13 3 50,0 0 3 1 1 50,0 100,0 1
Haemophilia B 3 1 5 1 33,3 0 1 0 0 33,3 100,0 1
Lesch-Nyhan (HPRT) 1 1 2 0 0,0 0 0 0 0 0,0 0,0 0
Wiskott-Aldrich Syndrome 1 1 1 1 100,0 0 1 0 0 100,0 100,0 1
Total X-linked 27 15 44 12 0 1 11 3 2 0 800 7
                         
SGD+HLA matching 159 88 165 41 39,0 7 34 8 11 32,4 38,6 18
HLA Matching only 38 18 46 9 33,3 1 8 3 3 29,6 44,4 2
Total 561 334 758 141 35,7 25 116 27 38 29,4 34,7 69






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