Taller 1 Bases genticas Casos prcticos Inheritance pattern

Taller 1: Bases genéticas. Casos prácticos.

Inheritance pattern? 61 9† 21 † 35 30 10 Dx 9 6 Dx 3 1 Fam 403 F Burkitt lymphoma Jaundice + fever, 10 days of evolution B cell lymphoma Colorectal cancer Hemophagocytic synd.

Duncan disease (OMIM#308240) 63 61 21 † + 30 35 _ + + 10 Dx 9 13 † Trafico + 6 Dx 3 1 + Fam 403 F Burkitt lymphoma Jaundice + fever, 10 days of evolution B cell lymphoma Colorectal cancer Hemophagocytic synd. 65 _ + 9† † 15 TBC † 38 parto † 80 +/- SH 2 D 1 A results † 3 † 16 Tifus I 93 65 II IV

Duncan disease. Characteristics The syndrome is characterized by extreme sensitivity to infection with Epstein-Barr virus, which results in a complex phenotype. Bone marrow transplantation is the definitive treatment of choice at the present time. Phenotype Cases (%) Mean age (years) Survival (%) ________________________________________ Fulminant mononucleosis 58 5 4 Lymphoproliferative disease 30 6 35 Dysgammaglobulinemia 31 9 55 Aplastic anemia 3 8 50 Vasculitis/Lymphoid granulomatosis 3 6, 5 29 Purtilo International X-linked Lymphoproliferative Disease Registry

Duncan disease. Preimplantational diagnosis 63 61 21 † 35 _ 65 _ + 9† † 15 TBC † 38 parto † 80 + 30 + 10 Dx 9 + Rec 14 Fam 403 F 13 † Trafico + 6 Dx 3 _ _ _ Burkitt lymphoma Jaundice + fever, 10 days of evolution B cell lymphoma Colorectal cancer Hemophagocytic synd. +/- SH 2 D 1 A results I 93 65 II III FN 11/08 1 + † 3 † 16 Tifus IV

X-linked recessive inheritance. Diseases Disease Gene Locus __________________________ Wiskott-Aldrich syn. WASP Xp 11. 22 -p 11. 23 X-linked lymphoproliferative dis. SH 2 D 1 A Xq 25 Diffuse leiomyomatosis with Alport syn. COL 4 A 5/COL 4 A 6 Xq 22 Androgen insensitivity AR Xq 11 -q 12

Inheritance pattern?

AD X-L AR

Familial Testotoxicosis (OMIM # 176410) INHERITANCE: Sex-limited autosomal dominant, luteinizing hormone receptor gene (LCGR), 2 p 21. CHARACTERISTICS: Precocious puberty, extremely rapid virilization.

Inheritance pattern? Possibilities? 53 44 18 16 15 2

Inheritance pattern? 53 44 18 - 16 15 2 Sporadic case? Autosomal recessive? Autosomal dominant, incomplete penetrance? Germinal mosaicism?

Inheritance pattern?

Mitochondrial inheritance

Inheritance of the mitochondrial genome Human cells usually contain thousands of copies of the doublestranded mt. DNA molecule. During zygote formation a sperm cell contributes its nuclear genome but only its mitochondrial genome to the egg cell. Consequently, the fertilized zygote contains only the mitochondria that were present in the unfertilized egg and are maternal in origin. Thus the mitochondrial genome is maternally inherited: males and females both inherit mitochondria from their mother, and males cannot transmit their mitochondria to subsequent generations. Thus a typical mitochondrially inherited condition can affect both sexes but is passed on only by affected mothers.

Inheritance pattern?

X-linked dominant inheritance, male-lethality

X-linked dominant inheritance, male-lethality Disease Gene Locus __________________________ Aicardi syndrome (OMIM#304050) ? Xp 22 It is characterized by a triad of callosal agenesis, infantile spasms, and chorioretinal lacunae ('holes'). Neoplasias: Hepatoblastoma, benign teratoma, embryonal carcinoma, metastatic angiosarcoma.

Inheritance pattern?

Y-linked inheritance Characteristics - Only male-to-male transmission. - All males affected. No women affected.

Y-linked inheritance Disease Gene Locus __________________________ Swyer syndrome (OMIM#306100) SRY Yp 11. 3 At birth patients with the XY female type of gonadal dysgenesis appear to be normal females; however, they do not develop secondary sexual characteristics at puberty, do not menstruate, and have 'streak gonads. ' They are chromatin negative and have a 46, XY karyotype. Neoplasias: Gonadoblastomas, germinomas.

Inheritance pattern? 45 22 7 5 Epilepsy, renal cysts, facial angiofibromas, brain hamartomas

Gonadal mosaicism 45 22 Tuberous sclerosis 7 5

Tuberous Sclerosis (OMIM#191100) Tuberous sclerosis complex is a dominantly inherited disease of high penetrance, characterized pathologically by the presence of hamartomata in multiple organ systems. Well known clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Many patients have renal lesions, usually angiomyolipomata, which can cause clinical problems secondary to hemorrhage or by compression and replacement of healthy renal tissue, which rarely causes end-stage renal failure. Cysts, polycystic renal disease, and renal carcinoma can also occur. Germline mosaicism occurs in about 2% of individuals with tuberous sclerosis complex 1. 1 Roach and Sparagana, J Child Neurol, 2004

Inheritance pattern? I II III IV

I X-linked dominant II IV I Autosomal dominant II IV

Inheritance pattern? 1 2 82 I 3 2 1 76 >70 II 2 1 56 3 4 11 5 16 13 6 dx 56 8 77 75 18 dx 66 19 dx 82 82 21 71 >50 III 17 3 49 50 dx 46 dx 49 (GC) 45 2 2 IV 20 40 36 30 22 46 44 dx 44 32 3 31 32 dx 39 V 3 24 22 1 30 dx 44 3 Bilateral clear cell renal carcinoma Unilateral clear cell renal carcinoma Gastric carcinoma 12 2 8 4 1 2 3 1 1 33 4 19 2 11 dx 80 42 5 26 dx 25 22 10 2 5

Familial CCRC. t(3; 8)(p 14. 1; q 24. 1) Menéndez et al, Hum Genet, 2003

1 2 82 I 3 2 1 76 >70 II 1 dx 56 56 2 3 75 dx 72 73 dx 70 72 4 11 NK 2 4 13 >85 8 45 2 2 NK 19 dx 82 21 71 >50 NK 17 IV 82 NK dx 46 dx 49 (GC) 49 18 77 dx 66 75 3 50 16 22 6 8 III NK 5 >60 20 40 36 22 30 46 44 dx 44 32 3 31 32 dx 39 NK NK 42 30 dx 44 3 NK dx 80 33 4 2 5 * NK 5 26 dx 25 V 3 24 22 12 2 8 4 1 2 19 2 1 NK 3 1 N K NK 11 10 1 NK • 19 translocation carriers identified Rodriguez-Perales et al, Hum Mol Genet, 2004 Valle et al, Eur J Hum Genet, 2005

1 2 82 I 1 3 2 76 >70 II 1 dx 56 56 2 3 75 dx 72 73 dx 70 72 4 11 NK 2 4 13 >85 8 45 2 2 NK 19 dx 82 21 71 >50 NK 17 IV 82 NK dx 46 dx 49 (GC) 49 18 77 dx 66 75 3 50 16 22 6 8 III NK 5 >60 20 40 36 22 30 46 44 dx 44 32 3 31 32 dx 39 NK NK 42 30 dx 44 3 NK dx 80 33 4 2 5 * NK 5 26 dx 25 V 3 24 22 12 2 8 4 1 2 19 2 1 NK 3 1 11 10 1 N K NK NK • 9 members have developed cc. RCC: 8 bilateral 1 unilateral forms All translocation carriers • 2 translocation carriers developed gastric ca. Valle et al, Eur J Hum Genet, 2005

1 2 82 I 1 3 2 76 >70 II 75 1 dx 56 56 2 3 75 dx 72 73 dx 70 72 4 11 NK 2 4 13 >85 8 45 2 2 NK 19 dx 82 21 71 >50 NK 17 IV 82 NK dx 46 dx 49 (GC) 49 18 77 dx 66 75 3 50 16 22 6 8 III NK 5 >60 71 20 40 36 22 30 46 44 dx 44 32 3 31 32 dx 39 NK NK 42 30 dx 44 3 NK dx 80 33 4 2 5 * NK 5 26 dx 25 V 3 24 22 12 2 8 4 1 2 19 2 1 NK 3 1 N K NK 11 10 1 NK • Of the carriers identified: 10 have not yet developed cc. RCC: 8 individuals : 10 -46 y/o 2 individuals: 75 and 71 y/o: INCOMPLETE PENETRANCE Valle et al, Eur J Hum Genet, 2005

Association with congenital malformations I 1 85* II 2 53 26 1 Family# 53 F 20 22 3 4 4 17 5 43 47 50 3 2 23 2 3 51 1 IV 72 77 1 III 2 7 6 5 15 5 7 8 6 18 9 16 10 42 7 9 11 33 8 40 9

Association with congenital malformations Probandus - A 19 -year-old male with abdominal pain and distension. Abdominal CT revealed multiple small cysts in liver, both kidneys and pancreas. A Polycystic Kidney Disease was diagnosed. - At the age of 20, pelvic osteolytic lesions were evident. Biopsy was consistent with a well-differentiated neuroendocrine tumour. - Extent evaluation: presacral mass (metastases? ). - MRI and PET revealed a wide dissemination of tumour lesions with bone marrow involvement. - No response to chemotherapy and the patient died at the age 22. - Necropsy: evidence of multi-organ involvement. Presacral mass: neuroendocrine tumour and teratoma. Minimal neural tube defect.

Probandus (IV-3) Pelvic CT Neural tube defect Metastatic osteolytic lesion M Presacral mass * Ascites (liver methastases)

Probandus (IV-3). Presacral mass section Areas of mature teratoma with scamous cysts * Malignant neuroendocrine component

Association with congenital malformations I 1 85* II 2 2 1 26 1 3 51 53 IV 20 22 23 2 3 4 4 17 5 Probandus Age on the upper right corner 43 47 50 3 Currarino syndrome * 72 77 1 III 2 7 6 5 15 5 7 8 6 18 9 16 10 42 7 9 11 33 8 40 9

Currarino syndrome (OMIM#176450) Features - Anorectal anomalies Chronic constipation - Sacral malformations Hemisacrum to minimal coccygeal alterations - Presacral mass Meningocele, teratoma, other Inheritance - AD, variable expressivity, incomplete penetrance - HLXB 9 (7 q 36) mutations

Patient IV-11 (first cousin) Pelvic CT Sacral dysrhaphism with a large anterior and posterior sacral defect M Presacral mass is placed between the two halves of the sacrum and is compressing the rectum

Patient III-6 (paternal uncle) Pelvic CT and MRI Abnormal morphology of the sacral bone M Cystic and septated presacral mass (benign teratoma) R Rectum Coccyx completely horizontal

Currarino syndrome (OMIM#176450) I 1 II 1 85* - 1 26 IV 1 - 2 3 51 + 23 - 77 + 2 53 III 2 20 22 3 + 4 + + 3 4 17 5 + 7 6 HLXB 9 study results, lower right corner Probandus * Age, upper right corner 43 47 50 Currarino syndrome -/+ 2 - 5 15 5 7 8 - 6 18 9 - 16 10 + 42 + 7 9 11 72 - + 33 8 40 9

Saggital MR images Patients III-2 (a: father), IV-5 y IV-4 (b, c: brothers) Presacral masses (benign teratomas) Enlarged and tilted coccyx (a and b) and normal coccyx © R Rectum P Prostate

Currarino syndrome. Oncologic risk

† 80 dx 45 61 † 60 dx 59 38 Dx 35 † 79 dx 67 † 58 Dx 35, 45 34 dx 30 Breast cancer Prostate cancer Bilateral breast cancer Pancreas cancer Ovary cancer 81 dx 69 33 dx 33 30

Incomplete penetrance † 80 dx 45 BRCA 1+ 61 BRCA 1+ † 58 Dx 35, 45 BRCA 1+ 38 Dx 35 BRCA 1+ BRCA 1 - † 79 dx 67 BRCA 1 - BRCA 1+ 34 Dx 30 BRCA 1+ Breast cancer Prostate cancer Bilateral breast cancer Pancreas cancer Ovary cancer 81 dx 69 BRCA 1 - 33 Dx 33 BRCA 1+ 30 BRCA 1 -

† 80 dx 45 BRCA 1+ 61 BRCA 1+ † 58 Dx 35, 45 BRCA 1+ 38 Dx 35 BRCA 1+ BRCA 1 - † 79 dx 67 BRCA 1 - BRCA 1+ 34 Dx 30 BRCA 1+ Breast cancer Prostate cancer Bilateral breast cancer Pancreas cancer Ovary cancer 81 dx 69 BRCA 1 - 33 Dx 33 BRCA 1+ 30 BRCA 1 -

Phenocopy. Sporadic case † 80 dx 45 BRCA 1+ 61 BRCA 1+ † 58 Dx 35, 45 BRCA 1+ 38 Dx 35 BRCA 1+ BRCA 1 - † 79 dx 67 BRCA 1 - BRCA 1+ 34 Dx 30 BRCA 1+ Breast cancer Prostate cancer Bilateral breast cancer Pancreas cancer Ovary cancer 81 dx 69 BRCA 1 - 33 Dx 33 BRCA 1+ 30 BRCA 1 -

† 34 † 75 43 45 † 7 20 Café-au-lait spots Neurofibromas Lisch nodules CNS tumour? Rhabdomyosarcoma 18 19 14

NF 1. Variable expressivity † 34 † 75 43 45 † 7 20 Café-au-lait spots Neurofibromas Lisch nodules CNS tumour? Rhabdomyosarcoma 18 19 14

FAP. Intrafamilial variability 69 ? I: 2 67 I: 1 50 II: 1 II: 2 75 I: 3 26 III: 1 III: 2 Affected I: 6 63 dx 44 51 II: 4 II: 5 2 32 III: 3 70 I: 5 II: 3 + 31 dx 21 73 I: 4 28 III: 4 11 IV: 1 III: 6 + 3 31 III: 5 44 dx 36 II: 6 29 III: 7 III: 8 25 29 III: 10 16 III: 11 III: 12 17 III: 13 7 IV: 2 >100 polyps Desmoid Sebaceous cysts Patient II-4 with a profuse form of FAP (>1000 polyps) and sebaceous cysts at the age of 15. Patient II-3 has the first symptom (desmoid) of the disease at the age of 61.

Textbooks Genetics - Harper PS. Practical Genetic Counselling. Oxford University Press, sixth edition, 2004 - Nussbaum R, Mc. Innes R, Willard H. Thompson & Thompson Genetics in Medicine. 7 edition. Saunders, 2007 Hereditary Cancer - Eeles RA, Easton DF, Ponder BAJ, Eng C. Genetic predisposition to cancer. Oxford University Press, second edition, 2004 - Vogelstein B, Kinzler KW. The Genetic Basis of Human Cancer. Mc. Graw-Hill, second edition, 2002 Genetic Glossary - Glosario de Genética http: //www. institutoroche. com/glosario. php? paraula 1=a Databases Genetics Online Mendelian Inheritance In Man http: //www. ncbi. nlm. nih. gov/sites/entrez? db=omim Associations Genetics Asociación Española de Genética Humana (AEGH) www. aegh. org