heterozygous missense mutations in smarca2 cause ... · heterozygous missense mutations in smarca2...

Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome

Jeroen K. J. Van Houdt, Beata Anna Nowakowska, Sérgio B. Sousa, Barbera D. C. van

Schaik, Eve Seuntjens, Nelson Avonce, Alejandro Sifrim, Omar A Abdul-Rahman, Marie-

José H. van den Boogaard, Armand Bottani, Marco Castori, Valérie Cormier-Daire, Matthew

A. Deardorff, Isabel Filges, Alan Fryer, Jean-Pierre Fryns, Simone Gana, Livia Garavelli,

Gabriele Gillessen-Kaesbach, Bryan D. Hall, Denise Horn, Danny Huylebroeck, Jakub

Klapecki, Malgorzata Krajewska-Walasek, Alma Kuechler, Matthew A. Lines, Saskia Maas,

Kay D. MacDermot, Shane McKee, Alex Magee, Stella A. de Man, Yves Moreau, Fanny

Morice-Picard, Ewa Obersztyn, Jacek Pilch, Elizabeth Rosser, Nora Shannon, Irene Stolte-

Dijkstra, Patrick Van Dijck, Catheline Vilain, Annick Vogels, Emma Wakeling, Dagmar

Wieczorek, Louise Wilson, Orsetta Zuffardi, Antoine H. C. van Kampen, Koenraad Devriendt,

Raoul Hennekam, Joris Robert Vermeesch

Nature Genetics: doi:10.1038/ng.1105

Supplementary Table 1: Clinical features of the 44 NBS patients included in this study.

Patients NBS01 NBS02 NBS03 NBS04 NBS05 NBS06 NBS07 NBS08Patientnr - reference - 1 - - 2 - Pat 3 - 3 4SMARCA2 exon affected ex25 ex25 ex25 ex25 ex25 ex18Phenotype - groupa 1 1 2 1 1 1 1 1Epidemiology

Origin Jewish Belgian Dutch Belgian Polish Polish S. African / N. Irish British

Sex M F M F M M F F Age (years)b 21 20 9 2.9 19 23 7.3 32 Age father/mother (years)c 27/29 25/25 28/29 44/42 26/22 28/29 32/29 39/23Growth At birth (weeks gestation) 40 35 36 37 40 37 39+5 40- Weight, g (SD) 3600 (0) 2100 (-0.5) 1395(<-3) 1830 (-2.5) 1900 (<-3) 2750 (0) 2420 (-2.5) 1800 (<-3)- Length, cm (SD) 50 (-1.5) 46.5 (0) 42.5(<-3) 42.5 (<-3) 48 (-1) 53 (+1) 49 (-0.5) ?- OFC, cm (SD) ? 31 (-0.5) 31 (-1) 31 (-1,5) 32 (<-3) 33 (0) ? ? Post-natal (years) 1 20 7.9 3 19 12.9 6.1 32- Weight, kg (SD) 6 (<-3) 39(-2.5) 18.6 (-2.5) 10.7 (-2) 50 (<-2) 25 (<-2) 18.05 (-1) 58 (0)- Height, kg (SD) ? 169(+1) 120.5 (-1) 81 (<-3) 158 (-2.5) 141.5 (-2) 111.4 (-1) 135 (<-2)- OFC, cm (SD) ? 53 (-1) 49 (<-2) 46.5 (<-2) 52 (<-2) 48.5 (<-2) 49.9 (-1) 51.8 (-2)Development Delay (degree)d +++ +++ +++ +++ +++ +++ +++ +++ Sat/walked independently (months) ?/26 ?/? ?/30 18/10 8/24 13/19 8/14 6/18 Speech - first words (months) ? ? late none 36 24 none 24 Seizures (age years) - − - +(1.7) - +(2) +(1.6) +(3)Craniofacial features- Low anterior hairline ? - + - + + + -- Sparse hair + + + + + + + + - Prominent eyelashes - − + + - + + -- Triangular face (childhood) + + + - + + + +- Increased skin wrinkling + + + + + + - +- Sagging periorbital skin + + - + + - + +- Narrow palpebral fissures - − + - + + + +- Down slant palp. fissures - − - - - - - -- Narrow nasal bridge - + + - + + - +- Upturned nasal tip + + + + + + + +- Thick alae nasi + + + + + + + +- Broad nasal base + + + - + + + +- Broad philtrum + + + + + + + +- Long philtrum + (+) + + - + + +- Large mouth + + + + + + + +- Thin upper vermillion - + + + + + - +- Thick lower vermillion + + + + + + + +- Widely spaced teeth - − + + + + + +Trunc and limbs- Scoliosis - + - - ? + - +- Cryptorchidism + n.a. - n.a. + - n.a. n.a.- Umbilical/inguinal hernia + − - + + - - -- Prominent IP joints - + + + + + + +- Prominent distal phalanges - + + + + + - + - Fetal finger pads + ? + - ? + + (feet) +- Sandal gap ? ? - + + + + -Radiology- Bone age nl del ? nl adv ? adv adv- Cone-shaped epiphysis ? ? - - - ? - +- Short metacarpals/tarsals ? −/− +/- +/- +/+ ? +/- +/+- Short phalanges ? − - - + - - -Other

- Cardiac defect - − - - - PDA+ASD - -

- Vesico-ureteral reflux - − - - - - - +- Poor mammary develop - + - - - - n.a. +- Eczema + + - - - + + +Karyotype ? nl ? nl nl nl nl nl

arrayCGH ? nl ? nl nl nl nl nl

4) Nicolaides, P. & Baraitser, M. An unusual syndrome with mental retardation and sparse hair. Clin Dysmorphol 2, 232-6 (1993)5) Castori M., Covaciu C., Rinaldi R., Grammatico P., Paradisi M. A rare cause of syndromic hypotrichosis: Nicolaides-Baraitser syndrome. J Am Acad Dermatol. 59 (5 Suppl) :S92-8 (2008).6) Gana S. et al. Nicolaides-Baraitser syndrome: two new cases with autism spectrum disorder. Clin Dysmorphol. 20(1):38-41 (2011).

1) Witters I., Fryns JP. Mental retardation, sparse hair, facial dysmorphism with a prominent lower lip, and lipodystrophy. A variant example of Nicolaides-Baraitser yndrome? Genet Couns 14: 245–247 (2003)

a) phenotypic groups: 1 - certain NBS clinical diagnosis. 2 – NBS uncertain clinical diagnosis (degree of certainty established by experience). b) at present or when reported. c) at time of birth. d) developmental delay degree: +++ severe; ++ moderate; + mild. N, northern; S, southern; ex, exon; M, male; F, female; OFC, occipito-frontal circumference; IP, inter-phalangeal; del, delayed bone age; adv, advanced bone age; nl, normal; n.a., not applicable; PDA, persistent ductus arteriosus; ASD, atrial septal defect; PFO, persistent foramen ovale; VST, Ventricular septum thickness; MVI, mitral valve insufficiency; DAA, double aortic arch; PAS, pulmonary artery stenosis (left); abn BCT, abnormal brachio-cephalic trunk.

2) Krajewska-Walasek M., Chrzanowska K., Czermiska-Kowalska A. Another patient with an unusual syndrome of mental retardation and sparse hair? Clin Dysmorphol 5: 183–186 (1996)3) Sousa, S.B. et al. Nicolaides-Baraitser syndrome: Delineation of the phenotype. Am J Med Genet A 149A, 1628-40 (2009).


NBS09 NBS10 NBS11 NBS12 NBS13 NBS14 NBS15 NBS16 NBS17 NBS18 NBS19Pat 4 - 3 Pat 5 - 3 - - - Pat 1 - 3 Pat 16 - 3 - - - -

ex25 ex25 ex18 ex25 ex25 ex19 ex15 on 24 +2 intron ex24 ex181 1 2 1 1 1 1 2 2 1 1

British British Polish Morrocan Polish British British Dutch N Irish Italian N African

M M M F F M M M F M F8.4 12.1 6 10 21 9 3 16 10 11.3 4.8

30/35 36/32 23/29 36/27 25/24 25/24 42/35 45/41 ?/23 34/51 39/37

41+3 38 40 41 40 39 35 35 term 42 402820 (-1.5) 3400 (0) 3200 (-0.5) 3850 (+0.5) 3160 (-0.5) 3700 (+0.5) 2090 (-1) 2250 (-0.5) 3580 (0) 3300 (-1) 2500 (-2.5)

47 (-2) 52 (+1) 54 (+1) ? 54 (+2) ? ? 43.5 (‐1.5) ? ? ?32 (-3) ? 35 (0) ? 32 (-2) ? 34.5 (+1.5) ? ? ? ?7.11 12 5.2 10 21 9.4 3 16 9.3 11.3 4.4

21 (-1.5) 23.3 (<-2) 14.9 (-1.5) 41 (+0.5) 51.4 (-0.5) 30 (0) 10.2 (-2.5) 30 (<‐2) 30.2 (+0.5) 39.5 (0) 12.1 (-2.5)118.5 (-1.5) 127.8 (-3) 103 (-1.5) 135 (-0.5) 159.3 (-0.5) 128.7 (-1) 83 (<-3) 1.51 (‐3) 125 (-1.5) 148 (+0.5) 93.5 (-2.5)

49.6 (-2) 52.1 (-1) 51.6 (0) 52.3 (0) 50.5 (<-2) 50.3 (<-2) 49.2 (-0.5) 50 (<‐2) 53.4 (+0.5) 53 (-0.5) 46.4 (<-2)

+++ +++ +++ ++ +++ ++ +++ +++ +++ +++ +++9/24 6/15 18/26 6/12 6/12 10/16 9/26 ?/18 24/48 ?/15 24/48none 18 (lost) 15 18 none 24 none none 48 none none+(1.2) +(2.6) - - +(1) - +(1.1) + (3) + (8) +(18) +(1.8)

+ + + + + + + - + + ++ + + + + + + + + + ++ - + + + - + + + + ++ + + + + + + + +/- + +/-+ - - + - + + + + - -- - - + - + + - + - +- - - + - - - - - + -- + + - - - - + + + -+ - + + + + - + - + ++ - - - - + + + + - ++ + + + + + + + + + +- + + - - + + + + + ++ + + + + + + + + + ++ + - + - + + + + + -- + + + + + + + + + ++ + + + - + + - - - -+ + + + - + + + + + -+ - + + - + + + + ? +

- - + - - - - + - - -+ + - n.a. n.a. + + + n.a. + n.a.+ - + + - - + + - + -+ + - + + + + + + + +- + - + + + - - + - -

+ (feet) + + ? - + - - + - ++ + + ? + - - - + + +

del nl adv ? nl del del ? ? - nl- - - ? + - + ? - + -

-/- +/- ? +/? -/+ +/- -/- ? -/- -/+ -/-- - + ? + + + ? - - -

- DAA ASD - - - - ? - - -

- - - - - - - ? - - -n.a. n.a. - n.a. - n.a. n.a. ? ? n.a. -+ + + - - + - dry skin - - +nl nl nl nl nl nl nl nl nl ? ?

nl ? nl nl nl nl - nl intragenic dystrofin del ? ?


NBS20 NBS21 NBS22 NBS23 NBS24 NBS25 NBS26 NBS27 NBS28 NBS29 NBS30- Pat 2 - 3 Pat 12 - 3 Pat 17 - 3 Pat 6 - 3 Pat 7 - 3 - Pat 10 - 3 - Pat 13 - 3 Pat 14 - 3

ex18 ex24 ex25 ex24 ex15 ex15 ex18 ex18 ex18 ex18 ex191 1 1 1 1 1 1 1 1 1 1

French British Turkish Bangladeshi N American N American N American German German Swiss French

F M M M F F M M M M F11 2.3 13.7 6.9 4.8 4.8 4 16 ? 3.9 16

29/29 18/20 39/39 29/26 31/26 31/26 ?/? 26/25 ?/? 19/20 30/23

39 39 40 40 36 36 38 term ? 38 402,940 2520 (-2) ? 2115 (<-3) 1955 (-1.5) 1445 (<-3) 3150 (0) 2500 (-2) ? 2540 (-1) 2520 (-2)

48 ? ? ? ? ? 51 (+0.5) 46 (-2) ? 45 (-2.5) 45 (-3)34 34 (0) ? 31 (<-3) ? ? 33.5 (-0.5) 33 (-1) ? ? 33.5 (-0.5)11 1.9 11 2.1 2.4 2.5 2.9 16 17 3.6 15

25 (-1) 8.89 (-2.5) ? ? 9.8 (-2) 10.6 (-1.5) 13.8 (0) 31 (-2) 56 (-1) 10 (<-3) 42 (-1)136 (-1.5) 77.2 (-2.5) 129 (-2) 82 (-2) 85 (-1) 84 (-1.5) 99 (+1) 144 (<-3) 157 (-2.5) 92 (-2) 152 (-1.5)52 (-0.5) 48.4 (-0.5) 52.1 (-1) 47.5 (-1) 44.7 (<-2) 45 (<-2) 49 (-0.5) 53 (-2) ? 47.8 (<-2) 51 (<-2)

++ +++ +++ +++ +++ +++ + +++ +++ ++ ++?/25 12/- 6/10 ?/20 9/16 9/14 ?/? ?/30 ? ?/12 ?/1824 none 10 (lost) none 24 24 late none ? 45 24- - +(0.9) +(0.7) +(0.9) +(3) - +(1.6) ? - +(2)

+ + + + - - + + + - ++ + + + + + + + + + ++ + + + - - + - - + ?+ + ? + + + - + ? - ++ - - + - - + + - - -+ + - - + + + + + + ++ - + - - - - + + - ++ - - - - - + + (+) - ++ + + + - - - - + - ++ + + + + + +/- + - + -+ + + + + + + + (+) + ++ + + + + + + + - + ++ + + + + + + + + - ++ + + + + + + + + + ++ + + + + + + + + + +- + - + + + + + + - ++ + + + + + + + + + ++ - - - - - + + + + -

? - - - - - - - ? - +n.a. - + - n.a. n.a. - + ? - n.a.

- - - + - - + + ? - -+ - - + + + + + ? - +- + - - + + - + ? + -+ + + - + + ? + ? + -- + + - + + ? - ? - +

? del adv nl ? ? ? del ? del ?? - - - + + ? - ? - -? -/- +/- -/- -/- -/- ?/? +/- ? -/- +/+? - + - - - ? + ? - -

- PFO+VST+MVI - - - - - - ? - -

- - - - - - - ? ? - -- n.a. n.a. n.a. n.a. n.a. n.a. n.a. ? n.a. ++ - + - - - + - ? + -? nl nl nl nl nl nl nl nl nl nl

? nl nl - nl nl nl nl - nl -


NBS31 NBS32 NBS33 NBS34 NBS35 NBS36 NBS37 NBS38 NBS39 NBS40 NBS41Pat 15 - 3 Pat 18 - 3 - 5 - - - - - - -

ex25 ex18 ex25 ex15 ex24 ex19 ex251 1 1 1 1 2 1 1 1 2 2

Morrocan / Algerian German Polish Italian N American Belgian Belgian Canadian Italian Dutch German

F F M F M M M M M M M17.1 13 11 9 ? ? 17 2.11 13 12 11

32/32 26/30 28/23 29/32 21/21 36/25 44/42 ?/? 30/24 ?/? 40/?

40 40 ? (39) 40 39 40 ? (39) ? 35 (twin) 40 412600 (-2) 3000 (-0.5) 2950 (-0.5) 2060 (<-3) 2800 (-0.5) 3000 (-1) 3160 (0) ? 2340 (-0.5) 3200 (-0.5) 2990 (-1.5)47 (-1.5) 51 (+0.5) 53 (+1) 46 (-2.5) 49 (-0.5) 47 (-2) 52 (+0.5) ? 47 (0) ? 52 (0)

34 (0) 33.5 (-0.5) 33 (-1) 33 (-1) ? 32 (-3) ? ? 35 (+3) ? 34 (-1)17 13 10 8.7 11.3 3.25 16 2.11 13 5.6 6.1

55 (0) 30 9-1.5) 26 (-1) 20 (-2) 36.8 (-0.5) 11 (-2.5) 47 (-1) 11.89 (-1.5) 33 (-1.5) 15.8 (-1) 17 (-1.5)154 (-1) 152 (-0.5) 127 (-2) 121 (-1.5) 124.6 (-2.5) 86.5 (-3) 168 (-0.5) 95 (0) 141.5 (-2) 101.5 (-2.5) 104 (-2.5)54 (-0.5) 52 (-1) 49.5 (<-2) 49.5 (-2) 53.5 (-0.5) 45.9 (<-2) 54.5 (-1) 49.2 (-0.5) 49.5 (<-2) 54 (+2) 48 (<-2)

+++ +++ ++ ++ ++ +++ + +++ ++ ++ +++?/17 11/21 8/18 6/17 09//21 ?/14 ?/17 ?/2 ?/2.6 ?/2.6 18/6014 36 24 19 10 late late 31 72 54 none

+(1.6) - +(3) - +(1.3) - - +(0-2) - - + (1.5)

+ - - + + - - + - + ++ + + + + + - + + - ++ + - + + + + - - + -? + - - + - + + + - ++ - - - + - - - + - -- + - - + + + + + + -+ - - - - - + - - - +- - + - + - + - + - ++ - + + - - - - + - +- + - + - + + + - + ++ + - + - + + - - + ++ + + + + + + + - + ++ + - + + + + + - + +- + - + ? + - + - + +- + + + + - + + + + ++ + + + + + + - + - ++ + + + + + + + - + +- + - - + - + + + - +

+ + + - - - - - + - -n.a. n.a. + n.a. + - - - - - +

- - + + + - - - - - -- + + + + - + - + - +- + - + + + + - + - +- + + - - - ? + ? + -+ + - + + + ? - + + -

nl nl del nl del nl ? ? nl nl del- - - - - - ? ? + - -

+/- -/- -/- +/- -/- +/? +/? ? -/- -/- -/-- + - + - - ? ? - + -

- - - ASD+PAS PS+LVH - - - abn BCT MVI -

- - - - + + - - ? ? -- n.a. n.a. n.a. n.a. - - n.a. n.a. n.a. n.a.- + - - + - + + ? ? +nl nl nl nl nl nl nl nl nl ? nl

nl nl - - nl nl nl nl Xq28 gain mat ? nl


NBS42 NBS43 NBS44Pat 8 - 3 Pat 2 - 6 Pat 1 - 6

ex25 ex18 ex181 1 1

Dutch Italian Italian

M F F7 15 13

29/31 ? ?

39 36 403350 (0) 2000 (-1.5) 2900 (-1)

? 46 (-0.5) 49 (-0.5)? 31 (-1) 34 (0)7 11 10

19.3 (-2.5) 30 (-0.5) 29 (-0.5)116.4 (-1) 135 (-1.5) 126 (-2)49.9 (-1.5) 50.5 (-2) 49.5 (<-2)

+ +++ +++9/19 10/20 8/1824 36 36- +(1) +(1.3)

+ - -+ + ++ + ++ + ++ - -+ - +- - ++ - +- + -+ + -+ - ++ - ++ - -+ + -+ + ++ + +- + ++ + +

+ + -+ n.a. n.a.+ - -- + ++ + +- - -+ + +

del nl nl- - -

-/- +/- +/+- - -

- - -

- - -n.a. ? ?

- - -nl nl nl

nl nl nl


1

Supplementary Table 2: SMARCA2 variations observed in the control group (dbSNP132, 1000 Genomes Project, 223 genomes form the Genome of the Netherlands chr pos name exon ref variation function AA change 9 2029018 rs10964468 2 G A/G untranslated‐5 9 2029119 GoNL* 2 C C/T nonsynonymous p.Pro33Ser 9 2029196 rs10964470 2 G A/G synonymous 9 2029199 rs10964471 2 G A/G synonymous 9 2039572 rs61736900 4 G A/G synonymous 9 2039593 GoNL* 4 G G/T synonymous 9 2039761 rs13296982 4 A A/G synonymous 9 2039776 rs13296987 4 A A/G synonymous 9 2039779 rs113070757 4 CAG ‐/CAG deletion/insertion 9 2039779 rs62639301 4 G A/G synonymous 9 2039793 rs62534884 4 A A/C nonsynonymous p.Gln228Pro 9 2039809 rs34035317 4 ‐ ‐/GCA deletion/insertion 9 2039827 rs10964525 4 G A/G synonymous 9 2039860 rs62639302 4 A A/G synonymous 9 2056706 rs76764591 5 A A/G nonsynonymous p.Asp403Gly 9 2056829 rs35724685 5 ‐ ‐/G deletion/insertion 9 2058305 rs7020514 6 T G/T nonsynonymous p.Ser454Arg 9 2073292 rs13288443 11 A A/G synonymous 9 2073295 rs111606727 11 A A/G synonymous 9 2073324 rs112486521 11 G A/G nonsense p.Trp62* 9 2096706 rs78915420 18 A A/T nonsynonymous p.Tyr978Phe 9 2110399 rs62534896 24 C C/T synonymous 9 2115920 rs78868042 25 C C/T synonymous 9 2116029 rs10137 25 G G/T nonsense p.Glu122* 9 2116037 rs6601 25 G A/G/T nonsynonymous p.Glu1224Asp 9 2119524 rs1803765 26 G G/T nonsynonymous p.Asp1251Tyr 9 2123799 rs61736902 27 C C/T synonymous 9 2123928 rs78274023 27 G A/G synonymous 9 2161793 rs61736901 28 A A/C nonsynonymous p.Lys1363Asn 9 2182194 rs1803766 31 C A/C synonymous 9 2186113 rs111380592 32 C C/T synonymous 9 2186224 rs77070978 32 C C/T synonymous 9 2191309 rs2296212 33 C C/G nonsynonymous p.Asp1546Glu 9 2191388 rs61736899 33 G A/G nonsynonymous p.Asp1573Asn 9 2191396 rs61761955 33 G A/G synonymous 9 2192877 rs75720779 34 C C/T untranslated‐3 9 2193040 rs3215772 34 T ‐/T untranslated‐3 9 2193116 rs75297871 34 C A/C untranslated‐3 9 2193121 rs78428567 34 G A/G untranslated‐3 9 2193170 rs17387924 34 G A/G untranslated‐3 9 2193359 rs7048532 34 T C/T untranslated‐3 9 2193437 rs45616134 34 T C/T untranslated‐3 9 2193455 rs1061478 34 A A/G untranslated‐3 9 2193465 rs28374302 34 T C/T untranslated‐3 9 2193571 rs74587303 34 C A/C untranslated‐3

* Variants only observed in the GoNL (Genome of the Netherlands) data set


2

Supplementary Fig. 1: Amino acid alignment of the human SMARCA2 gene and its homologues in Pan troglodytes (chimpanzee), Canis familiaris (dog), Bos taurus (cow), Mus musculus (mouse), Rattus norvegicus (rat), Gallus gallus (chicken), Danio rerio (zebra fish), Caenorhabditis elegans and Saccharomyces cerevisiae (yeast). The positions are shaded according to their conservation across taxa; red = conserved, white= intermediate, blue = variable. The snf2 family conserved ATPase domain is marked with a dark grey background.


3


4

Supplementary Fig. 2: Immunohistochemical detection of Smarca2 in the developing mouse brain and skin. (a-j) Smarca2 is present at several stages during mouse brain development. (a, b) Postmitotic neurons in the cortical plate (E14.5) produce high levels of Smarca2 (Sigma Prestige antibody). (c) At E15.5, Smarca2 levels in the cortical plate remain high (Abcam antibody) (d) Available mouse gene expression data from Genepaint also show high level expression of Smarca2 in the postmitotic regoin of the cortex (e, f). Smarca2 levels drop at E16.5 as shown by immunostaining using two independent antibodies (e: Sigma Prestige; f: Abcam) (g) At E18.5, the signal is confined to a subpopulation of deep layer neurons in the area of cortical layer 5. (h, i) A similar signal in the area of layer 5 is found at P0 (j) In the adult brain, clear Smarca2 labeling is detected in the cortex and the hippocampus, whereas the dentate gyrus (DG) contains less positive cells, and the oligodendrocytes in the corpus callosum (CC) are not stained. (k) In the skin, Smarca2 is present in the epithelial layer of early hair follicles (arrowhead) but less in the condensing mesenchyme (double arrowheads) at E16.5. (l) In the skin, the Abcam antibody shows intense staining of nearly all cells of the epithelium and the condensing mesenchyme. (m) In later stage hair follicles Smarca2 is still high in the epithelium (arrowhead) touching the papilla (double arrowhead). Scale bars are 200 �m in all except in l: 100 �m. Abbreviations: VT: ventral telencephalon, CP: cortical plate, MZ: marginal zone, CC: corpus callosum, DG: dentate gyrus


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