Aggrecan (ACAN) mAggrecan (ACAN) mthe clinicathe clinica

Mutaciones en Autac o es eespectro clínp

K E HKaren E. He

Instituto de Genética Médicla Unidad Multidisciplinar de Di

H it l U i it i L P UAM Id

UMDE

mutations: expandingmutations: expandingal spectrumal spectrum

Aggrecan (ACAN): gg eca ( C )nico ampliadop

th PhDeath, PhD

ca y Molecular (INGEMM) y isplasias Esqueléticas (UMDE), iPAZ & CIBERER ISCIII M d id S i

• Aggrecan is a large chondroitin sulphategg g pproteoglycan

• 250 kDa protein core with approximatelychondroitin sulphate glycosaminoglycan keratan sulphate chains attached to a larlocated between three globular domains

• It is expressed in several tissues includinbrain but is a major structural componenbrain, but is a major structural componenin the cartilage extracellular matrix in the– Growth plate– Articular cartilageArticular cartilage– Intervertebral discs

• Function is to allow the cartilage to withsgmechanical load found in the skeletal join

d

y 100 and 30 rge domain .

ng those in the nt of cartilagent of cartilage e:

stand the high gnt

• Spondyloepiphyseal dysplasia, Kimberley type (SEDK) ADKimberley type (SEDK) – AD

• Familial osteochondritis dissecans – AD

• Spondyloepimetaphyseal dysplasia, aggrecan type (SEMD) - ARaggrecan type (SEMD) - AR

Tompson et al, 2004;

D

• 103 individuals (20 families) with shomild facial dysmorphismsmild facial dysmorphisms.

S• Some had distinct phenotypes showispurt and early growth cessation orp y gand precocious osteoarthritis.

J Clin Endocrinol Metab 2017;102(2):460-469)

ort stature, minor skeletal defects and

ing advanced bone age, poor pubertalothers with osteochondritis dissecans

•SKELETALSEQ V1 - 226 geJan 2012 SKELETALSEQ.V1 226 ge

SKELETALSEQ V2 295

Jan 2012

•SKELETALSEQ.V2 - 295 geDec 2012

•SKELETALSEQ V3 315 geMar 2014 •SKELETALSEQ.V3 - 315 geMar 2014

•SKELETALSEQ V4 - 327 geFeb 2015 •SKELETALSEQ.V4 - 327 geeb 0 5

Oct 2015 •SKELETALSEQ.V5 - 362 geOct 2015

SKELETALSEQ V6 368Feb 2016 •SKELETALSEQ.V6 - 368 geFeb 2016

•SKELETALSEQ.V7 - 385 geJan 2017

enes (Roche)enes (Roche)

H l l A il t t h l i )enes Haloplex, Agilent technologies)

enes (Roche SeqCap MiSeq) 16/runenes (Roche SeqCap, MiSeq) - 16/run

enes (MiSeq) -18/runenes (MiSeq) -18/run

enes (MiSeq) -18/run

(N tS ) 80/enes (NextSeq) - 80/run

enes (NextSeq) - 80/run

heterozygous A

14 mild to moderate short stature and bframeshift) Those with osteoarthritis anframeshift). Those with osteoarthritis an

2 Spondyloepiphyseal dysplasia, Kimbe

ACAN mutations

rachydactyly (missense, nonsense and d/or discopathyd/or discopathy.

erley type (SEDK)

Delayed bone age (n=4) BA=CADelayed bone age (n=4) BA=CA

Height (cm) Height (cm)

Weight (kg)

Median height SDS in childreng

A (n=5) Advanced BA (n=5)A (n=5) Advanced BA (n=5)

Height (cm)

Weight (kg) Weight (kg)

n was -2.91 (range -4.30/-1.86 SDS)( g )

Pediatric cohort

• 53% of patients have a mild dysmo53% of patients have a mild dysmo

23% frontal bossing depressed na• 23% frontal bossing, depressed na

orphic phenotypeorphic phenotype

sal bridge and mid face h poplasiasal bridge and mid-face hypoplasia

Probands and adults showing brachyd

Brachydactyly and first short metBrachydactyly and first short met

dactyly and/or short first metacarpal.

tacarpal, present in all cases.tacarpal, present in all cases.

• 38% had mild hip anomaliesCoxa valga, slender femor

Coxa valga, mildly flattened capital emoral epiphyses and slender femora

a b ca b c

23% had mild epiphyseal knee defect

Short femoral necks ra

dd

ts

Study reference

er o

f pa

dren

/adm

X fa

m

SGA

of h

eigh

Child

ren

Adul

ts

ance

d B

child

ren

ntal

bos

nasa

l br

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from

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e o C

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n

ilsson et al, 2014 14 (5/9)*3 fams 2/4

-4/-1.2-3.8/-2.3 3/5 NR NR

uintos et al, 2015 3 (1/2)**1 fam 0/1 -2.7

-4.7/-2.6 1/1 NR NR

Manouk van der Steen et al, 2016

10(4/6)

3 fams3/3 -3.7/-2.4

-5.4/-3.7 3/4 NR NR 9

kourogianni et al, 2017

102(32/70)

20 fNR -4.2/-0.6

-5.9/-0.9 19/23 2/32 8/20 82017 20 fams 5.9/ 0.9

Dateki et al, 2017

4 (2/2)1 fam 0/2 -2.7/-2.5

-3 1/-3 2/2 NR NR2017 1 fam -3.1/-3Hu et al,

20179(3/6)3 fams 1/1 -4.3/-2.9

-5.4/-2.9 0/3 NR NR

Hauer et al,2017

11(6/5)6 fams 1/6 -3.9/-2 -

3.8/-1.8 2/5 3/6 NR

32 Current study

32 (14/18)14 fams

4/13 -4.3/-1.86-5.4/-1.79 5/13 5/13 4/13 3

SUMMARY

164(59/105) 11/40 -4.7/-0.6 30/45 9/49 4/13 2

cial h

ypo

chyd

ac

umbs

, ast

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ac

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reat

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6/9 6/9 3/9 NR NR NR NR 5/5 1/3 0/3

1/3 NR NR NR NR NR NR 2/2 0/1 0/1

9/10 NR 3/10 6/10 3/10 NR NR NR 3/3 0/3

8/20 5/20 3/20 NR NR NR NR 23/70 13/20 8/20

3/4 NR NR NR 1/4 NR NR NR 0/1 1/1

NR NR NR NR NR NR NR NR 0/3 0/3

NR 3/6 2/6 2/6 NR 1/6 NR NR 1/6 NR

3/13 12/13 11/13 NR 3/13 5/13 3/13 6/6 3/14 1/14

22/39 19/28 19/38 8/16 7/27 5/13 3/13 27/74 20/45 10/39

• Premature termination codons potepor haploinsufficiency through nonse

Dominant negative (neo morphic) m• Dominant-negative (neo-morphic) mcartilage structure and function

entially resulting in truncated proteins y g pense mediated mRNA degradation

missense mutations that disruptmissense mutations that disrupt

• Expands the clinical and molecular s• Expands the clinical and molecular smutations.

• Strong candidate in patients with sh• Strong candidate in patients with shand not only those with advanced bo

li ticomplications.

• Hand, knee and hip anomalies shoub i di ti f thibe indicative of aggrecanopathies.

spectrum of heterozygous ACANspectrum of heterozygous ACAN

ort stature and minor skeletal defectsort stature and minor skeletal defects one age and osteoarticular

uld be carefully observed as they can

Spanish ACAN studySpanish ACAN study• Lucía Sentchordi-Montané, Miriam Aza-Car

Bonis María Consuelo Sánchez Garre PabBonis, María Consuelo Sánchez-Garre, PabLechuga-Sancho, Atilano Carcavilla-Urquí, Moreno Ángela del Pozo Elena Vallespín AMoreno, Ángela del Pozo, Elena Vallespín, ASergio B. de Sousa, Purificación Ros-Pérez

Dysplasia research group• Miriam Aza, Jimena Barreza, Carlos Rivera,

Sara Benito, Maria Rodriguez, Beatriz Paum

INGEMMINGEMM• NGS y Arrays: Elena Vallespin, Vicky F. Mon• Genética Clínica y prenatal: Fernando Sant• Genética Clínica y prenatal: Fernando Sant

Elena Mansilla, Fe Santiago• Bioinformática: Ángela del Pozo Kristina IbBioinformática: Ángela del Pozo, Kristina Ib

Skeletal dysplasia multidisciplinary unit (UM• Fernando Santos (coordinador), Ana Coral

Gaspar González, Manuel Parrón, Eugenia A

UMDE

mona, Sara Benito-Sanz, Ana Barreda-blo Prieto Matos Pablo Ruiz Ocaña Alfonsoblo Prieto-Matos, Pablo Ruiz-Ocaña, Alfonso

Inés Mulero-Collantes, Gabriel A. Martos Amaka Offiah Manuel Parrón-PajaresAmaka Offiah, Manuel Parrón-Pajares, z, Isabel González-Casado, Karen E. Heath

, Lucia Sentchordi, Alberta Belinchón, mard, Carolina de la Torre

ntaño, Maria Palomares, Julian Nevado os Sixto García-Miñaur Pablo Lapunzinaos, Sixto García-Miñaur, Pablo Lapunzina,

bañez Juan Carlos Silla Mario Solísbañez, Juan Carlos Silla, Mario Solís

MDE), Hospital La Paz Barreda y Isabel González, Rima Regojo, Antolín, Marta Cabrera