Sotos syndrome. Nazneen Rahman Institute of Cancer Research

Transcription

1 Sotos syndrome Nazneen Rahman Institute of Cancer Research

2 Sotos syndrome- background Sporadic condition Distinctive facial appearance Overgrowth (tall with big heads) Learning difficulties Other variably present features congenital heart disease renal anomalies seizures tumours

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5 NSD1 identification

6 FISH analysis showing microdeletion in Sotos cases

7 Intragenic NSD1 mutations in Sotos cases Kurotaki et al Nature Genetics 30, (2002)

8 NSD1 mutations and deletions UK/Europe/USA - 77% NSD1 mutations - 10% 5q35 microdeletions Japan - 14% NSD1 mutations - 50% 5q35 microdeletions

9 NSD1 Nuclear receptor-binding SET domain-containing protein 1

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11 NSD1 methylates H4 K20 and H3 K36

12 Childhood Overgrowth Study Cases 530 cases ascertained overgrowth and/or facial similarity with Sotos All screened for NSD1 mutations and deletions 266 NSD1 mutations / deletions

13 Childhood overgrowth study Evaluation of 266 NSD1+ve cases Spectrum of NSD1 abnormalities 266 NSD1 positive cases 91 frameshift mutations 59 nonsense mutations 64 missense mutations 11 splice site mutations 8 partial gene deletions 33 5q35 microdeletions

14 NSD1 mutations in Sotos syndrome Truncating mutations NID -L NID PWWP -I PHD -I PHD -IV N=150SAC +L PWWP -II SET PHD -V Exon Missense mutations N=64 P=2x10-12

15 Missense mutations only occur in functional domains (P=2x10-12 )

16 Missense mutations mostly occur at conserved residues

17 5q35 microdeletions 33 5q35 microdeletion cases identified Ranged in size from ~0.4Mb (1 gene deleted) to ~5Mb (54 genes deleted) At least 8 different sizes Four, and possibly 18 in total, may have arisen through NAHR

18 REPcen BD NSD1 REPtel BD D5S400, a SOT21, SOT32, SOT31, SOT30, SOT29, SOT28, SOT26, SOT12, SOT27, SOT1, FGFR4, c SOT3, SOT19, SOT26, SOT25, D5S2008, SOT24, SOT23, D5S2073, COG025 b D d U D D D D D D D U D COG231 U D D D D D D D D D D D D D D U D D COG342 U D D D D D D D D D D D D D D U N U COG183 U U U N D D D D D D D D U U U COG070 U U U U D D D D D D D D D COG064 N U U D D D D D D N D U COG547 N N U N U U D D N U N N N COG218 U N N U U U D D D N U U COG347 U D D D D D D D D D D COG344 U D D D D D D D D D D COG172 U U U U U D D D U U U COG548 U U U N D U D D N U N COG177 U U U U U U D D U U U COG179 U U U U U U D D U U U COG211 U U U U U U D D U U U COG146 U U U U U U D D U U U COG160 U U U U U D D U U U COG346 D D D D D D D D D D COG343 D D D D D D D D D D COG184 U D D D D D D D D U COG330 U U U U U D D U U U COG532 N U U D D N U U U U U COG395 U U D D U U N U U U COG450 N U U D D N N U COG512 N U U D D N U U COG399 U U U U D D U U U COG340 U U D D D D D D COG044 U U U D D D COG508 e D D D D D COG345 U D D COG367 D D COG111 D 5Mb, 54 genes 480kb, 1 gene

19 Non-allelic homologous recombination 400kb 325kb 46kb

20 Parent of origin of deletion 18/21 (86%) paternally inherited 5q35 deleted. 3/21 (14%) maternally inherited 5q35 deleted There is a strong bias towards deletion of the paternal allele. P=0.0015

21 Male vs Female recombination rates on chromosome 5 NSD1

22 Partial gene deletions 8 cases with partial gene deletions Alu repeat elements flanked 4 cases which are likely generated through NAHR 4 cases involved exons 1 and 2 Remaining four cases each involved different exons

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24 Contribution of NSD1 to Sotos syndrome 136 UK NSD1-positive cases All 136 were scored as definite Sotos or Sotoslike 136 cases included 75 truncating mutations (55%) 35 missense mutations (24%) 4 splice site mutations (3%) 7 partial gene deletions (5%) 15 5q35 microdeletions (11%)

25 Contribution of NSD1 to Sotos syndrome Additional nine UK NSD1-negative cases were scored as classic Sotos syndrome NSD1 abnormalities were detected in 94% of Sotos cases Of which 89% were intragenic mutations and 11% were 5q35 microdeletions

26 Cardinal Features of NSD1 Facial gestalt - 99% Intellectual impairment - 97% Severe 21% Moderate 46% Mild 30% None 3% Overgrowth (Height +/or OFC >98 th ) - 90%

27 Major Features of NSD1 : analysis of 239 NSD1+ve cases Advanced bone age - 76% Cranial MRI/CT abnormalities - 76% Neonatal problems (transient) - 70% Scoliosis - 32% Seizures - 24% Cardiac anomalies - 21% Maternal pre-eclampsia - 17% Renal anomalies - 15%

28 Other Features of NSD1 : analysis of 239 NSD1+ve cases astigmatism behavioral problems cataract cholesteatoma conductive hearing loss constipation contractures craniosynostosis cryptorchidism gastro-esophageal reflux genu valgum hemangioma hemihypertrophy hydrocele hypercalcemia hypermetropia hyperpigmentation hypopigmentation hypoplastic nails hypospadius hypothyroid inguinal hernia myopia neonatal hypoglycemia nystagmus pectus excavatum phimosis strabismus talipes 2/3 toe syndactyly tumors umbilical hernia vertebral anomalies

29 Comparison between 5q35 microdeletions and mutation cases 221 mutation cases and 31 microdeletions. Compared growth, intellectual impairment, cardiac, renal, seizures, scoliosis. Compared phenotype of cases with different sized deletions. Evaluated whether any features seen only in deletion cases.

30 Comparison between 5q35 microdeletions and mutation cases Microdeletion cases tend to be smaller and have more severe learning difficulties than mutation cases.

31 Comparison of growth in 5q35 microdeletion vs mutations

32 Comparison of intellectual impairment in 5q35 microdeletions vs mutations P=3x10-9

33 Comparison between 5q35 microdeletions and mutation cases Microdeletion cases tend to be smaller and have more severe learning difficulties than mutation cases. No correlation between deletion size and phenotype. All clinical features seen in deletion cases were also seen in mutation cases. NSD1 haploinsufficiency is responsible for the phenotype of 5q35 microdeletions. Most severe Sotos cases have intragenic mutations

34 Other genotype-phenotype analyses No significant differences between phenotypes of truncating and missense mutations. No correlation between position of mutation and phenotype.

35 Contribution of NSD1 to other phenotypes Analysed 530 of cases with broad phenotypes. Photographs of 290 cases reviewed independently by 3 Geneticists, blinded to the molecular results. Only 2/166 NSD1+ve cases were inconsistent with clinical diagnosis of Sotos. 62/64 definitely not Sotos cases were NSD1 negative. NSD1 specific for Sotos syndrome and doesn t cause other phenotypes.

36 NSD1 and Weaver syndrome No classic Weaver case with NSD1 mutation. Three atypical Weaver cases previously reported with NSD1 mutations were reclassified as Sotos. Weaver and Sotos have clinical overlap and testing should be done in all?weaver cases. If NSD1 mutation found, manage as for Sotos. Weaver is now a diagnosis of exclusion.

37 Algorithm of the suggested approach to a child/adult with suspected Sotos syndrome Facial appearance consistent with Sotos syndrome and Height and/or head circumference >98th centile and/or learning disability Yes No NSD1 mutation analysis NSD1 abnormality detected NSD1 abnormality not detected All three initial clinical categories fulfilled Yes No Sotos syndrome Sotos syndrome is unlikely Manage as Sotos syndrome Consider other diagnoses

38 History Detailed general history with particular emphasis placed upon symptoms of known complications of Sotos syndrome eg: Dysuria, haematuria, increased frequency of micturition Concerns about development, speech and hearing Suggested approach at the initial evaluation of an individual diagnosed with Sotos syndrome Examination blood pressure cardiac auscultation spine exam for scoliosis growth parameters Investigations urine dipstick echoardiogram renal ultrasound scan Abnormality detected No abnormality detected Specialist referral Organise review for one to two years time

39 History Detailed general history with particular emphasis placed upon symptoms of known complications of Sotos syndrome eg: Dysuria, haematuria, increased frequency of micturition Concerns about development, speech and hearing Examination blood pressure cardiac auscultation spine exam for scoliosis growth parameters Algorithm for the suggested surveillance of NSD1- positive/classic Sotos syndrome cases Routine Investigations urine dipstick repeat renal ultrasound scan if diagnosis of Sotos syndrome made <5years of age Abnormality detected No abnormality detected Organise further relevent investigations (eg echocardiogram, renal ultrasound scan) and referral to appropriate specialist Organise next review for one to two years time

40 Implications for families We analysed 303 unaffected parents, including both parents in 141 cases. All were negative. >90% of Sotos cases have de novo NSD1 aberrations. No case with non-penetrance. No case of germinal mosaicism. Recurrence risk is very low. Offspring risk is in theory 50%, but only 12 families.

41 NSD1 and Sotos syndrome what we know Sotos syndrome is a relatively common overgrowth condition caused by NSD1 abnormalities. >90% Sotos cases have identifiable NSD1 aberrations. NSD1 does not cause other overgrowth conditions. Recurrence risk is very low as most occur de novo. Cancer risk is low, no screening indicated. Cardiac anomalies, renal anomalies and scoliosis need monitoring.

42 NSD1 and Sotos syndrome what we don t know Very broad phenotypic variability even in cases with the same mutation why? Limited prognostic information. Why are so few familial Sotos cases if offspring risk is 50% as predicted. What causes the NSD1 negative classic Sotos cases How does NSD1 haploinsufficiency cause overgrowth and other features of Sotos syndrome. What genes underlie non-sotos overgrowth.

43 Acknowledgements Kate Tatton-Brown Trevor Cole Valerie Cormier-Daire Jenny Douglas Karen Temple Seval Turkman Helen Hughes Francesca Faravelli Childhood Overgrowth Consortium Leeds Spain representing individuals from: Birmingham Leicester Australia Aberdeen KGC Southampton Manchester France GOS Nottingham Liverpool Oxford Austria St Georges Belfast Bristol Edinburgh USA Guy s Dundee Dublin Saudi Arabia Canada Cardiff Cambridge Exeter Belgium Switzerland Newcastle Sheffield Glasgow Germany Israel