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1 Supplementary Online Content Tan TY, Dillon OJ, Stark Z, et al. Diagnostic effect and cost-effectiveness of whole-exome sequencing of ambulant children with suspected monogenic conditions. JAMA Pediatr. Published online July 31, doi: /jamapediatrics etable. Clinical Phenotype and Genotype of Children Diagnosed by WES (n = 23) This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable. Clinical Phenotype and Genotype of Children Diagnosed by WES (n = 23) ID Clinical phenotype (HPO terms) Diagnosis Gene Variant(s) Zygosity Inheritance [HP: ] Short stature [HP: ] Microcephaly [HP: ] Delayed speech and language development [HP: ] Synophrys [HP: ] Long philtrum [HP: ] Anteverted nares [HP: ] Microcephaly [HP: ] Scoliosis [HP: ] Generalized hypotonia [HP: ] Synophrys [HP: ] Hirsutism [HP: ] Bruxism [HP: ] Constipation [HP: ] Sleep disturbance [HP: ] Short stature [HP: ] Microcephaly [HP: ] Strabismus [HP: ] Umbilical hernia [HP: ] Intellectual disability, severe [HP: ] Generalized hypotonia [HP: ] Short stature [HP: ] Microcephaly [HP: ] Synophrys [HP: ] Thin vermilion border [HP: ] Long philtrum [HP: ] Preauricular pit [HP: ] Intellectual disability, moderate [HP: ] Clinodactyly of the 5th finger [HP: ] Delayed closure of the anterior fontanelle Cornelia De Lange Syndrome [OMIM ] Bainbridge-Ropers Syndrome [OMIM ] Autosomal recessive spastic paraplegia type 51 [OMIM ] KBG syndrome [OMIM ] NIPBL NM_ :c.5471C>T;p.(Ser1824Leu) Heterozygous De novo ASXL3 NM_ :c.1207C>T;p.(Gln403*) Heterozygous De novo AP4E1 ANKRD1 1 NM_ :c.3277C>T;p.(Gln1093*) NM_ :c.2129G>A;p.(Trp710*) NM_ :c.3224_3227delCTTT;p.( Glu1075Glyfs*242) Compound heterozygous Heterozygous AR De novo

3 [HP: ] Decreased body weight [HP: ] Short stature [HP: ] Intellectual disability, severe [HP: ] Generalized hypotonia [HP: ] Delayed CNS myelination [HP: ] Low-set ears [HP: ] Deeply set eye [HP: ] Hypotelorism [HP: ] Microcephaly [HP: ] Intellectual disability, mild [HP: ] Hirsutism [HP: ] Conductive hearing impairment [HP: ] Obesity [HP: ] Tall stature [HP: ] Ventricular septal defect [HP: ] Hypospadias [HP: ] Intellectual disability, mild [HP: ] Bifid uvula [HP: ] Short digit [HP: ] Progressive muscle weakness [HP: ] Hepatomegaly [HP: ] Elevated serum creatine phosphokinase Mental retardation, autosomal dominant [OMIM ] Rubinstein-Taybi Syndrome [OMIM ] Acrodysostosis 2, with or without hormone resistance [OMIM ] Glutaric acidemia type IIC [OMIM ] TBL1XR 1 NM_ :c.557C>T;p.(Ser186Leu) Heterozygous De novo EP300 NM_ :c.1407delA;p.(Ala470Leu*8) Heterozygous De novo PDE4D NM_ :c.388T>C;p.(Phe130Leu) Heterozygous De novo ETFDH NM_ :c.1456insT;p.(Leu486Profs*4 ) NM_ :c.1238C>T;p.(Ser413Phe) Compound heterozygous AR

4 [HP: ] Downslanted palpebral fissures [HP: ] Sparse eyebrow [HP: ] High-arched palate [HP: ] Anteverted nares [HP: ] Medial flaring of the eyebrow [HP: ] Low posterior hairline [HP: ] Ptosis [HP: ] Posteriorly rotated ears [HP: ] Low-set ears [HP: ] Prominent fingertip pads [HP: ] Pectus carinatum [HP: ] Scoliosis [HP: ] Mild global developmental delay [HP: ] Wide intermamillary distance [HP: ] Inverted nipples [HP: ] Decreased body weight [HP: ] Short stature [HP: ] Wide mouth [HP: ] Long palpebral fissure [HP: ] Horizontal nystagmus [HP: ] Brachydactyly syndrome [HP: ] Joint hypermobility [HP: ] Feeding difficulties [HP: ] Moderate global developmental delay [HP: ] Seizures [HP: ] Abnormality of pain sensation [HP: ] Central hypotonia [HP: ] Hyperacusis Coffin Siris Syndrome 2 [OMIM ] Mental retardation, autosomal dominant [OMIM ] ARID1A NM_ :c.2367_2368delGCinsTT Heterozygous De novo TBL1XR 1 NM_ :c.976A>C;p.(Ser326Arg) Heterozygous De novo

5 [HP: ] Deeply set eye [HP: ] Horizontal eyebrow [HP: ] Short philtrum [HP: ] Nystagmus [HP: ] Esotropia [HP: ] Abnormality of the pinna [HP: ] Large earlobe [HP: ] Recurrent lower respiratory tract infections [HP: ] Intellectual disability, severe [HP: ] Bruxism [HP: ] Sleep disturbance [HP: ] Dystonia [HP: ] Chorea [HP: ] Head titubation [HP: ] Abnormality of the globus pallidus [HP: ] Constipation [HP: ] Hirsutism [HP: ] Muscular hypotonia of the trunk [HP: ] Short stature [HP: ] Truncal obesity [HP: ] Delayed puberty [HP: ] Long palpebral fissure [HP: ] Short 4th metacarpal [HP: ] Short fifth metatarsal [HP: ] Short 3rd metacarpal [HP: ] Short 5th metacarpal [HP: ] Short fourth metatarsal [HP: ] Autism spectrum disorder [HP: ] Intellectual disability [HP: ] Seizures Mental retardation, autosomal dominant 8 [OMIM ] Albright hereditary osteodystrophy-like Syndrome [OMIM ] GRIN1 NM_ :c.1676A>G;p.(Gln559Arg) Heterozygous De novo PRMT7 NM_ :c.312delG;p.(Lys105Argfs*2 2) NM_ :c.1159A>G;p.(Arg387Gly) Compound heterozygous AR

6 [HP: ] Decreased body weight [HP: ] Short stature [HP: ] Talipes [HP: ] Patellar dislocation [HP: ] Dislocated radial head [HP: ] Brachydactyly syndrome [HP: ] Abnormality of the thumb [HP: ] Kyphoscoliosis [HP: ] Deeply set eye [HP: ] Micrognathia [HP: ] Long philtrum [HP: ] Thin upper lip vermilion [HP: ] Frontal bossing [HP: ] Hypertelorism [HP: ] Brachycephaly [HP: ] Downturned corners of mouth [HP: ] Wide nasal bridge [HP: ] Bilateral single transverse palmar creases [HP: ] Talipes equinovarus [HP: ] Ulnar deviated club hands [HP: ] Metatarsus adductus [HP: ] Bilateral camptodactyly [HP: ] Clinodactyly of the 5th finger [HP: ] Distal arthrogryposis [HP: ] Microcephaly [HP: ] Low hanging columella [HP: ] Submucous cleft soft palate [HP: ] Downslanted palpebral fissures Spondyloepiphyseal dysplasia with congenital joint dislocations [OMIM ] Aarskog-Scott Syndrome [OMIM ] Weidemann-Steiner Syndrome [OMIM ] CHST3 NM_ :c.1291dupA;p.(Ser431Lysfs* 81) Homozygous FGD1 NM_ :c.1171A>G;p.(Arg391Gly) Hemizygous XLR; mat KMT2A NM_ :c.3539G>C;p.(Gly1180Al a) Heterozygous AR De novo

7 [HP: ] Smooth philtrum [HP: ] Thin vermilion border [HP: ] Esotropia [HP: ] Hearing impairment [HP: ] Broad thumb [HP: ] Broad hallux [HP: ] Tapered finger [HP: ] Mild global developmental delay [HP: ] Generalized hypotonia [HP: ] Hirsutism [HP: ] Elbow hypertrichosis [HP: ] Sparse scalp hair [HP: ] Erythroderma [HP: ] Ichthyosiform abnormality of the skin [HP: ] Congenital nonbullous ichthyosiform erythroderma [HP: ] Eczema [HP: ] Gastroesophageal reflux [HP: ] Multiple cafe-au-lait spots [HP: ] Metaphyseal dysplasia [HP: ] Neutropenia [HP: ] Constipation [HP: ] Abnormal blistering of the skin [HP: ] Soft skin [HP: ] Delayed speech and language development Ichthyosis, congenital, autosomal recessive 6 [OMIM ] Schmid metaphyseal chondrodysplasia [OMIM ] Epidermolysis bullosa simplex, Ogna type [OMIM ] NIPAL4 NM_ :c.527C>A;p.(Ala176Asp) Homozygous AR COL10A 1 NM_000493:c.1945C>T;p.(Gln649*) Heterozygous De novo PLEC NM_ :c.5998C>T;p.(Arg2000Trp) Heterozygous AD (inherited from affected mother)

8 [HP: ] Short stature [HP: ]Sparse eyebrow [HP: ] Hypoplasia of dental enamel [HP: ] Biparietal narrowing [HP: ] Macrodontia of permanent maxillary central incisor [HP: ] Overfolded helix [HP: ] Broad finger [HP: ] Small feet [HP: ] Broad hallux [HP: ] C1-C2 vertebral abnormality [HP: ] Intellectual disability, mild [HP: ] Hypoplastic nipples [HP: ] Hypertrichosis [HP: ] Neonatal hypotonia [HP: ] Sparse scalp hair [HP: ] Coarse facial features [HP: ] Absent speech [HP: ] Severe global developmental delay [HP: ] Hypoplastic fifth fingernail [HP: ] Hypertrichosis Weidemann-Steiner Syndrome [OMIM ] Coffin-Siris Syndrome 1 [OMIM ] KMT2A ARID1B NM_ :c.2312delC;p.(Pro773Arg fs*8) NM_ :c.3555dupC;p.(Ser1186Leufs *24) Heterozygous Heterozygous De novo De novo

9 [HP: ] Microcephaly [HP: ] Hypotelorism [HP: ] Broad nasal tip [HP: ] Abnormality of the nares [HP: ] Upslanted palpebral fissure [HP: ] Unilateral microphthalmos [HP: ] Coloboma [HP: ] Strabismus [HP: ] Prominent ears [HP: ] Large earlobe [HP: ] Abnormality of the pinna [HP: ] Abnormality of the plantar skin of foot [HP: ] Subcutaneous lipoma [HP: ] Sacral dimple [HP: ] Clinodactyly of the 5th finger [HP: ] Intellectual disability, severe [HP: ] Bruxism [HP: ] Spasticity, progressive [HP: ] Constipation [HP: ] Short stature [HP: ] Macrocephaly [HP: ] Elevated hepatic transaminases [HP: ] Abnormality of lipid metabolism [HP: ] Hepatomegaly [HP: ] Nystagmus [HP: ] Congenital nuclear cataract [HP: ] Severe global developmental delay [HP: ] Dystonia Mental retardation, autosomal dominant 19 [OMIM ] Glycogen storage disease IXa1 [OMIM ] Autosomal recessive spastic paraplegia 46 [OMIM ] CTNNB1 PHKA2 NM_ :c.2050delA;p.(Arg684Glufs* 51) NM_ :c dupG [2.8 kb del chrx: 18,912,524-18,915,343 identified on custom PCR and Sanger sequencing confirmation] Heterozygous Hemizygous GBA2 NM_ :c.1495G>A;p.(Glu499Lys) Homozygous AR De novo XLR

10 [HP: ] Hypertonia [HP: ] Arachnoid cyst Legend: AD autosomal dominant; AR autosomal recessive; HPO Human Phenotype Ontology; OMIM Online Mendelian Inheritance in Man; XLR X-linked recessive.