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Genetic Bases of Short Stature Bases Genéticas De La Talla Baja

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Genetic Bases of Short Stature Bases Genéticas De La Talla Baja Genetic bases of short stature Bases genéticas de la talla baja Alexander A. L. Jorge The University of São Paulo, School of Medicine Genetic-Endocrinology Unit Brazil Buenos Aires - 2019 Nothing to disclose Genetic disorders A genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence G C Genetic defects Somatic Mosaicism Germline Types of genetic defects Chromosome abnormality • Numerical changes (aneuploidies) • Structural changes (chromosomal rearrangements) Most microduplication/deletion syndromes are ≥ 500 kb Miller et al . Am J Hum Genet 2010 ;86(5):749-64 Techniques for analysis Karyotype MLPA Resolution >4Mb Candidate locus/loci Genomic Molecular Karyotype FISH (SNP or CGH array) Candidate locus Resolution 20-50 kb Good for mosaicism Genomic Abnormalities at the nucleotide level if in the coding region@ Several other mechanisms Frameshift Inframe alteration Splicing Expression mRNA Stoploss . Feero et al N Engl J 2ed. 2010 %A62(21):2001-11 Abnormalities at the nucleotide level 1anger se uencing 2assive parallel se uencing (NG1) A candidate gene approach Chole exome or genome se uencing Good for specific variant Great for analyDing multiple regions 1mall genes simultaneously :ew candidate genes 2ore automated analysis AAA GGG TGG A AAA GGG TGG A T Katsanis & Katsanis . Nat 8ev Genet 201A%14(6):415-26 LetEs start with growth disorders Differential diagnoses of short stature Chronic systemic diseases 0 Endocrine conditions (hypothyroidism) 0 Celiac disease 0 Psychosocial deprivation 0 Primary and secondary undernutrition 0 Chronic kidney disease, 0 Gastrointestinal disease 0 8heumatologic disease, 0 Hematological, 0 Cardiac disease 0 Pulmonary disease, 0 2uscular and neurological disorders 0 2edication (glucocorticoid) Differential diagnoses of short stature Chronic systemic diseases G1H Disorders of the GH3IG: axis I2H 1yndromic short stature 5-,H 16eletal dysplasia I2H Isolated short stature (Jnormal variants of growthK) 960H 0 Idiopathic short stature 0 :amilial short stature 0 Constitutional delay of growth and puberty 0 Children born small for gestational age Collett-Solberg et al . Growth Horm IG: 8es. 2019 % 44:20-A2 Heritability of height Genetic Large family studies consisting of thousands of families have also estimated the heritability of height is between 0.79- 0.98 Shared environment Study with 45 twin cohorts (180,520 pairs 1-19 years old) This heritability is lower in early childhood, increasing Specific environment with age, reaching a estimated heritability of 0.68- 0.94 Jelenkovic et al. 1ci 8ep 2016 % 2A%6:284.6 Silventoinen et al. Twin 8es 2003 % 6(5):A..-408 Wu et al. European Journal of Human Genetics 2003 % 11(A), 2,1L2,4 Genetic regulation of growth Severe phenotype Height variation Monogenic conditions polygenic traits Height SDS < -3 Height SDS M 2 Non-syndromic (common) short stature 95.4% 99.6% 5,5AA L phenotypes for which the molecular basis is known A,A18 L phenotype under investigation 8,851 Clinical synopses: Nshort statureN O8 N1mall for gestational ageN O8 dwarfism O8 dwarf O8 Nintrauterine growth restrictionN O8 NIntrauterine growth retardationN O8 NPostnatal growth retardationN 8esults: 1,0.. entries 12H of inherited3genetic diseases have growth disorder as an important phenotype Updated May 1st, 2019 The common problem of rare diseases 8are diseases: those that affect G1: 1,500 to 1: 2,500 8are diseases > 80% of rare affect diseases are 6 to 10% of genetic the population Difficult 50% of people diagnosis with rare P diseases are Errors and children High cost Knight & Senior 2ed J Aust. 2006 % 185(2):82-A 2ain genetic conditions associated with short stature Defects affecting: 0 Chromosomal abnormalities and CNVs 0 GH3IG:s axis 0 Intracellular pathways 0 :undamental cellular processes (syndromic short stature) 0 Paracrine factors in the growth plate 0 Cartilage extracellular matrix (1keletal dysplasias) 0 Imprinting disorders Wit et al. EJE 2016 % 1,4(4):145-1,A to keep in mind that not always is genetic 1yndromic short stature Epigenetic Environment Genetic (Epimutation) :etal alcohol syndrome 1ilver-8ussell syndrome .p trisomy syndrome (11p.15 epimutation) 2ain genetic conditions associated with short stature Turner Syndrome Noonan Syndrome 45,X PTPN11 and variants HRAS KRAS NRAS SOS1 SOS2 BRAF RAF1 MEK1 MEK2 ... 1 in 2,000live female births 1 in 1,000 and 1 in 2,500 children 2ain genetic conditions associated with short stature Achondroplasia and hypochondroplasia Léri-Weill dyschondrosteosis FGFR3 SHOX 1 in 15,000 to 40,000 newborns Estimate prevalence: 1 in 1,000-2,000 Genetic influences on height High Monogenic disease (severe short stature) Penetrance Low (Influence on the phenotype) on (Influence 0.1% 1% 10% Allele frequency Rare Common Rare condition = Rare genetic variant with high penetrance McCarthy et al. Nat Rev Genet. 2008 ; 9(5):356-69 Manolio et al. Nature. 2009 ; 461(7265):747-53 Diagnostic process and pattern recognition 1hort-limb Typical phenotype Postnatal short stature Height 1D1 -4., Height 1D1 -A.5 CA 2.2 yeas 1H:H 1D1 R1A Hypertrophic Height 1D1 -4.8 8hiDomelic shortening cardiomyopathy Hypoglycemia Exaggerated lumbar lordoses Typical face :ather 184 cm Low nasal bridge 0 prominent forehead Trident hand 2other 162 cm 0 midface hypoplasia (Achondroplasia) (Noonan syndrome) (GHD) FGFR3 PTPN11, RAF1, ... > 20 genes Diagnostics not so simple 1GA (A. w% 2260 g) CA: .y Height 1D1 -2., (proportional) B2I 1D1 -0.A Delayed speech Language development disorder 1hort father (height 1D1 -2.5) Elevated IG:-1 (above 9 A 1D1) A candidate gene approach 1GA Height 1D1 -2., Language development disorder 1hort father (height 1D1 -2.5) Elevated IG:-1 (above 9 A 1D1) Could be a defect in the IGF1R leading a partial IGFs insensitivity? Normal IGF1R sequencing (21 exons) Normal IGF1 sequencing (6 exons) 2olecular karyotype in growth disorders Index patients with short stature of unknown origin N = 200 N = 149 Only born SGA Only born SGA N = 229 N = 51 N = 49 SNP array = 53 SNP array SNP array CGH array SNP array CGH array =166 Pathogenic or likely pathogenic CNVs N = 20 N = 17 N = 8 N = 8 N = 32 (10%) (11%) (15.7%) (16%) (14%) Zahnleiter et al . van Duyvenvoorde et al . Canton et al . Wit et al . Homma et al . PLoS Genet 2013 Eur J Hum Genet 2014 Eur J Endocrinol 2014 Horm Res Paediatr 2014 Horm Res Paediatr 2018 2olecular karyotype in growth disorders Homma et al. Horm 8es Paediatr 2018% 8.(1): 1A-21 An example of the use of the molecular 6aryotype A girl born 1GA Compatible with 22q11.2 Non-syndromic short stature De novo At the age of 11, she started deletion syndrome experiencing seiDures that were 22 11.2 (DiGeorge or velocardiofacial difficult control and without deletion syndrome) apparent cause Normal laboratory evaluation Normal echocardiogram 7aryotype 46,SS Absence of palatal alterations Normal immunology function Normal behavior Normal calcium, phosphorus and PTH rhGH (50 Tg36g3d) CA: 6.9 yr Height: 105.7 cm (-2.5 SD) BMI SDS = -1.5 Canton et al . Eur J Endocrinol 2014%1,1(2):25A-62 Genomic approach L CGH-array 1GA Height 1D1 -2., Language development disorder 1hort father (height 1D1 -2.5) Elevated IG:-1 (above 9 A 1D1) Could be pathogenic CNV? Normal molecular karyotype (SNP-array) Exome sequencing Human genome = 100% Exons – 1-2% of the genome (~ 3.235 Mb) (20,576 protein-coding genes) (~ 64 Mb) de Bruin & Dauber Nat 8ev Endocrinol 2015% 11(8):455-64 Using whole exome se uencing for the diagnosis of 2endelian disorders 2.000 patients (88H children and neurologic phenotype) Exome se uencing 708 mutated alleles that were highly likely to be causative in 504 patients ( 25%, 95% CI 23-27%) The success rate was higher when the family was evaluated (A1H) 4.6% received two non-overlapping molecular diagnoses Yang et al . JA2A 2014 %A12(18):18,0-18,. CE1 vs. traditional approach Dx P , V2,.050 Dx P 25 V6.00A Stark et al. Genet 2ed. 2017 % 1.(8):86,-8,4. Exome sequencing 44 patients born SGA with unknown syndromic short stature analyzed by WES BRCA1 – 3rd description BCL11B – 1st description PCNA – 2nd case 16:44 (36%) SRCAP (2x) positive findings ACTG1; AFF4, ANKRD11, CDKN1C, COL2A1, GINS1, INPP5K, KIF11, KMT2A, POP1A Homma, Freire et al. 1ubmitted (under review) 201. New genes under investigation Davor et al. Brain 2018 % 141(8):22..-2A11 Homma et al. Horm 8es Paediatr 2018 % 8.(1): 1A-21 Freire & Homma et al. Eur J 2ed Genet. 2018 % 61(A):1A0-1AA Genomic approach L CE1 1GA Height 1D1 -2., Language development disorder 1hort father (height 1D1 -2.5) Elevated IG:-1 (above 9 A 1D1) Exome sequencing: SRCAP (exon34) c. 7330C>T (p.R2444*) = Floating-Harbor syndrome Heterozygous de novo Homma, Freire et al. in preparation to be submitted 201. Isolated short stature SGA for length Healthy Short stature Absence of other findings Mother with short stature I. III.1 III.2 1. 155 cm 2. 160 cm Gestational age (ws) 38 Birth weight (kg) 2785 II. Birth length (cm) 44 1. 2. 3. 4. Age (y) 7.9 2.8 157 cm 164 cm 146.5 cm 189.8 cm Height (cm) 112.2 96 III. Height SDS -2.2 +1.2 1. 2. SH:H SDS +3.44 -1.2 Isolated short stature Apparently, isolated growth disorder Minimal laboratory evaluation Including IGF-1 (IGFBP-3), TSH/LT4, Celiac disease screening (+ karyotype for girls) Ce have to talk about Wrist x-ray for bone age genetic studyWWW Abnormal body proportions with normal or with unspecific findings in skeletal survey Familial short stature with dominant autosomal inheritance pattern Genetic regulation of growth Severe phenotype Height variation Monogenic conditions polygenic traits Height SDS < -3 Height SDS M 2 Non-syndromic (common) short stature 95.4% 99.6% 2ild phenotype of monogenic conditions? c.922A>G (p.Asn308Asp) c.417G>C (p.Glu139Asp) c.922A>G (p.Asn308Asp) PTPN11 mutations associated with Noonan syndrome 2ild clinical suspicion Children born 1GA III.1 0 A8 wee6s 0 2480 g ( -2.1 1D1) 0 4, cm ( -2.0 1D1) Normal head circumference Normal neurodevelopment Difficulty in school I.1 CA 8.
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