Non Traditional Inheritance

1. Non Traditional Inheritance

2. Traditional Inheritance Mendelian inheritance Diseases Single gene defects/disorders Autosomal inheritance Dominant e.g. Marfan�s syndrome Recessive e.g. Thalassaemia major X-linked recessive e.g. Haemophilia

3. Non-traditional Inheritance Polygenic or multifactorial inheritance E.g. Diabetes mellitus Mitochondrial inheritance E.g. Sensorineural hearing loss Genomic imprinting and uniparental disomy E.g. Prader-Willi Syndrome Trinucleotide repeat expansion E.g. Fragile X syndrome

4. Mitochondrial Inheritance

5. Mitochondrial DNA Mitochondria contain extranuclear DNA material (mtDNA) Inherited only from the mother, never from the father (paternal mtDNA lysed upon entrance of sperm into oocyte) Normally all mtDNA within an individual are identical mtDNA are prone to mutation

6. Mutation of mtDNA

7. Genomic Imprinting phenotypic expression depends on the parent of origin for certain genes and chromosome segments

8. Imprinting probably occurs in many different parts of the human genome but is thought to be particularly important in gene expression related to development, growth, cancer, evolution, and behavior.

9. What is genomic imprinting? Specific genes or DNA segments are reversibly modified during gametogenesis in a parent specific fashion. Parent of origin I.e. whether the specific gene is paternally / maternally inherited can be distinguished.

10. Parent of origin The parent specific genes can be epigenetically marked Epigenetically = gene structurally different but actual sequence of nucleotides is unchanged, e.g. methylation of the genes For imprinted gene, the gene expression and therefore the distinct functions depend on parent of origin.

11. Phenotypic expression of the imprinted genetic region depends on the parent of origin. Both paternal and maternal genetic regions are required for normal development. Prader Willi syndrome Angelman syndrome Beckwith-Wiedemann syndrome

12. PWS / AS Absence / dysfunction of imprinted region can occur by: Deletion Uniparental disomy mutation

13. Microdeletion Usually spontaneous Grandmatrilineal inheritance in PWS E.g. grandma with sporadic microdeletion, passes to her son as silent carrier. Her grandchildren will haave 50% chance of having PWS Likewise, grandpatrilineal inheritance in AS

14. Uniparental Disomy Inheritance of 2 copies of a particular chromosome form one parent and none from the other. The frequency of non-disjunctional events causing aneuploidy has been shown to increase dramatically with maternal age for most chromosomes Kupke et al. 1989, Hassold et al. 1995, 1996, Antonarakis et al. 1992.

15. Trisomy rescue Most trisomies are lethal, and the fetus survives only if a cell line loses one of the extra chromosomes post zygotally and becomes disomic. Robinson et al. 1996, Robinson et al. 2000 Monosomy duplication Monosomy followed by post-zygotic duplication of the single chromosome showed isodisomy for markers throughout the entire long arm of chromosome Gamete complementation Non-dysjunction in both parents i.e. 2 chromosomes from one parent and 0 from the other Mechanisms

16. The origin of UPD is caused by pre-zygotic non-disjunction followed by post-zygotic correction of the monosomic/trisomic zygote, both of which are spontaneous events. The recurrence of PWS or AS is probably non-significant in view of the rarity of UPD. Nicholls et al. 1989b, Malcolm et al. 1991, Smeets et al. 1992, Smith et al. 1997, Robinson et al. 2000

17. Non deletional mutations Effect: Lose ability for maternal to paternal or paternal to maternal switching. Site: Imprinting center Imprinting region Suggested to be due to a de novo imprint switch failure during parental gametogenesis and/or fertilization. Low recurrence risk.

18. Prader Willi Syndrome

19. Genetic Basis in PWS A sister disorder of Angelman syndrome Both result of the absence or lack of expression of one parent�s contribution to the same region of the proximal long arm of chromosome 15q, 15q11-q13. PWS �absence of paternally derived genes at 15q11-q13 AS�absence of maternally derived genes at 15q11-q13

20. Genetic basis in PWS Because of genetic imprinting, the maternally inherited genes are silent, I.e. not expressed / rendered inactive, likewise in AS. Grandmatrilineal inheritance

21. Genetic defects of PWS Absence of paternally derived genes at 15q11-q13 ~70% Paternal microdeletion ~25% Maternal uniparental disomy 2-5% Imprinting center defects

22. Maternal UPD was caused by a meiotic error in 90% of cases, of which 83% had arisen in the first meiotic segregation. Robinson et al. 1998b, Robinson et al. 2000, Robinson 2000 The frequency of uniparental disomy is much higher in Prader-Willi syndrome than in Angelman syndrome, obviously because of the relatively rare occurrence of meiotic non-disjunction in male compared to female meiosis. Martin et al. 1991, Antonarakis et al.1993b, Hassold et al. 1996).

23. Clinical features Many of the manifestations are related to functional hypothalamic deficiency Clinical appearance changes as the child grows.

24. Infantile period Central hypotonia can be severe Marked neonatal lethargy weak cry, decreased arousal, poor reflexes poor sucking and early FTT, which special feeding techniques e.g. special nipple / tube feeding may be needed to avoid severely impaired weight gain

25. Adults remain mildly hypotonic with decreased muscle bulk and tone. Short stature almost always present by the end of 2nd decade.

26. Global developmental delay GM: average of sitting 12m, walking 24m Delayed language development Poor academic performance

27. Hypogonadism Hypogonadotrophic hypogonadism Genital hypoplasia Male: cryptorchidism, scrotal hypoplasia, small penis Female: hypoplasia of labia minora / clitoris Pubertal insufficiency Male: some with no voice change, male body habitus and substantial facial or body hair Female: amenorrhoea, oligomenorrhoea, late menarche 30s sexual activity is rare, infertility is the rule.

28. Hyperphagia and obesity Hyperphagia likely of hypothalamic origin, manifest as lack of satiety Obesity commonly develops between 1-6 years, most often between 2-4. food seeking behavior, eating of unappealing substances A/w related obsessive behaviors PWS is the most common recognized genetic form of obesity. Obesity is a major cause of morbidity. e.g. garbage, pet food, frozen food like stealing food or stealing money to buy food is common Secondary to DM HT stroke sleep apnoeae.g. garbage, pet food, frozen food like stealing food or stealing money to buy food is common Secondary to DM HT stroke sleep apnoea

29. Cognitive impairment Usually Mild IQ mostly 60-70, 30% between borderline to average no evidence of IQ decline over time Unusual skill with jigsaw puzzles

30. Maladaptive Behavior variable but frequent, Common problems include Overeats, skin picking, stubborn, obsessions temper tantrums, disobedience, impulsivity, mood labiality, excessive sleep, talk too much, anxious and worried, withdrawal. Adapted from Dykens and Cassidy, 1999

31. Dysmorphic appearance narrow bifrontal diameter, almond shaped palpebral fissures, down-turned mouth with a thin upper lip Small hands with tapering fingers Hypopigmentation Strabismus Scoliosis, kyphosis

32. Genetic laboratory investigations Chromosomal analysis Florescence in situ hybridization analysis with 15q11-q13 specific probes Methylation analysis PCR and markers

33. Angelman Syndrome (AS)

34. Genetic defect of AS Deletion of 15q11-q13 region of maternal origin (70%) Chromosome 15 paternal uniparental disomy (UPD) (3%) Imprinting center mutation (1%) Intragenic mutation of maternal copy of UBE3A gene (6%)

35. Clinical features of AS Newborns have normal phenotype Developmental delay first noticed at around 6 months Other features manifest after 1 yr Diagnosis may take several years

36. Neurological Epilepsy 90% Delayed gross motor delvelopment Gait & movement Hyperkinetic movement Characteristic gait Cognitive level & speech Mental retardation, attention deficit, hyperactivity Understanding >>> expression Minimal to complete absent use of words

37. Characteristic Gait of AS Lean forward Uplifted arms Flexed elbow Downward turned hands Legs kept wide based Feet flat & turned outward

38. Behavioral Hyperactivity Short attention deficit Laughter & happiness �Happy-puppet� Reason unknown Early or persistent social smiling Sleep disturbance Reduced need for sleep

39. Musculoskeletal Microcephaly Brachicephaly Occipital groove Mandibular prognatism Widely spaced teeth

40. Genotype vs. Phenotype Patients with UPD/small deletion when compared with those of large deletion have: Later time of diagnosis Less severe epilepsy, later onset Less severe cognitive and speech impairment Better weight gain and occipital frontal circumference

41. Genetics laboratory tests Chromosome analysis Florescent in situ hybridization (FISH) Methylation test Paternal uniparental disomy (UPD) studies Ubiquintin-protein ligase E3A mutations Imprinting center (IC) mutations

42. Trinucleotide repeat expansion "An increased number of contiguous trinucleotide repeats in the DNA sequence from one generation to the next.� Fig. 1?Genetic locations of repeat expansions. The relative locations of known repeat expansions are portrayed on a prototypical gene. Expansions have been discovered in all regions of a gene. They are found in the upstream flanking region, as in episodic myoclonic epilepsy. They may occur in exons or in introns. Those that are present within exons may occur within the upstream untranslated region, as is found in fragile X syndrome; they may occur within the protein coding region, as is the case with Huntington disease; or they may occur within the downstream untranslated region, as is seen with myotonic dystrophy. There is one example of an intronic repeat expansion: Friedreich ataxia. The size of the triangles reflects the size of the triplet repeat expansion. EPM1 = episodic myoclonic epilepsy type 1; OPMD = oculopharyngeal muscular dystrophy; SCA = spinocerebellar ataxia; SBMA = spinal and bulbar muscular atrophy; DRPLA = dentatorubral-pallidoluysian atrophy.Fig. 1?Genetic locations of repeat expansions. The relative locations of known repeat expansions are portrayed on a prototypical gene. Expansions have been discovered in all regions of a gene. They are found in the upstream flanking region, as in episodic myoclonic epilepsy. They may occur in exons or in introns. Those that are present within exons may occur within the upstream untranslated region, as is found in fragile X syndrome; they may occur within the protein coding region, as is the case with Huntington disease; or they may occur within the downstream untranslated region, as is seen with myotonic dystrophy. There is one example of an intronic repeat expansion: Friedreich ataxia. The size of the triangles reflects the size of the triplet repeat expansion. EPM1 = episodic myoclonic epilepsy type 1; OPMD = oculopharyngeal muscular dystrophy; SCA = spinocerebellar ataxia; SBMA = spinal and bulbar muscular atrophy; DRPLA = dentatorubral-pallidoluysian atrophy.

43. Anticipation

44. Consequence of postzygotic changes in repeat length Consequence of incomplete penetrance Reversion of a repeat to a length below the disease threshold Expansion of a repeat from below to above disease thresholdConsequence of postzygotic changes in repeat length Consequence of incomplete penetrance Reversion of a repeat to a length below the disease threshold Expansion of a repeat from below to above disease threshold

45. Currently known expansion mutation disorders fall into 3 general groups.

46. 8 diseases caused by expanded CAG repeats encoding the amino acid glutamine. Clincial manifestation of thse diseases: may include abnormalities of voluntary and involuntary movement; dementia, affective, spychotic, or obsessive compulsive symptoms; apathy; irritability; and other less specific personility changes.Clincial manifestation of thse diseases: may include abnormalities of voluntary and involuntary movement; dementia, affective, spychotic, or obsessive compulsive symptoms; apathy; irritability; and other less specific personility changes.

47. Disease caused by relatively short repeat expansions. Synpolydactyly -abnormal skeletal patterning Cleodocranial dysplasia - disorder of skeletal development.Synpolydactyly -abnormal skeletal patterning Cleodocranial dysplasia - disorder of skeletal development.

49. Fragile X Syndrome

50. Genetics Verkerk in 1991 found the FMR-1 gene located at Xq27.3 Fragile X mental retardation gene 1 Normal population: FMR-1 varies from 5-50 repeats Premutation unaffected carriers: FMR-1 enlarges to up to 200 repeats. Affected patients: FMR-1 repeats more than a thousand times. Distal long arm of chromosome X at Xq27.3Distal long arm of chromosome X at Xq27.3

52. Physical manifestation Macroorchidism Large ears Prominent jaw Long face

53. Neurodevelopmental abnormalities Cognitive dysfunction Executive Visual-spatial Visual motor abilities Behavioral symptoms Autism Attention-deficit/hyperactivity disorder Social anxiety

55. References Margolis RL. Ross CA. Genetics of Childhood Disorders: IX. Triplet Repeat Disorders. J Am Acad Child Adolesc Psychiatry,38:12, 1598-1600 December 1999 Eliez S. Reiss AL. Genetics of Childhood Disorders: XI. Fragile X Syndrome. J Am Acad Child Adolesc Psychiatry, 39:2, 264-266 February 2000 Chiurazzi P et al. Understanding the biological underpinnings of fragile X syndrome. Curr Opin Pediatr 15:559-566 2003 Lombroso PJ. Genetrics of Childhood Disorders: XLVIII. Learning and Memory, Part 1: Fragile X Syndrome Update. J Am Acad Child Adolesc Psychiatry, 42:3 372-375 March 2003 McFarland R et al. The neurology of mitochondrial DNA disease. Lancet Neurology 1:343-51 2002 RenzoGuerrini et al. Angelman syndrome. Pediatr Drugs 5(10):647-667 2003 Wagstaff J et al. Genetics beyond Mendel. Postgraduate Medicine 108(3):131 September 2000