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Article: Green, C., Willoughby, J., Study, D.D.D. et al. (1 more author) (2017) De novo SETD5 loss-of-function variant as a cause for intellectual disability in a 10-year old boy with an aberrant blind ending bronchus. American Journal of Medical Genetics Part A, 173 (2). pp. 3165-3171. ISSN 1552-4825 https://doi.org/10.1002/ajmg.a.38461
This is the peer reviewed version of the following article: Green C, Willoughby J, DDD Study. Balasubramanian M. De novo SETD5 loss-of-function variant as a cause for intellectual disability in a 10-year old boy with an aberrant blind ending bronchus. Am J Med Genet Part A. 2017;173A:3165–3171, which has been published in final form at https://doi.org/10.1002/ajmg.a.38461. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
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[email protected] https://eprints.whiterose.ac.uk/ American Journal of Medical Genetics: Part A
De Novo SETD5 Loss-of-Function Variant as a Cause for Intellectual Disability in a 10-year old boy with an Aberrant Blind Ending Bronchus
For Peer Review Journal: American Journal of Medical Genetics: Part A
Manuscript ID 16-1145.R1
Wiley - Manuscript type: Clinical Report
Date Submitted by the Author: 11-Apr-2017
Complete List of Authors: Green, Claire; Sheffield Children's NHS Foundation Trust, Sheffield Clinical Genetics Willoughby, Joshua; Sheffield Children's NHS Foundation Trust, Sheffield Diagnostic Genetics Service Balasubramanian, Meena; Sheffield Children's NHS Foundation Trust, Sheffield Clinical Genetics Service;
3p microdeletion, SETD5, intellectual disability, aberrant blind ending Keywords: bronchus, loss of function
Search Terms: SETD5, clinical genetics, molecular genetics, genetic counselling
John Wiley & Sons, Inc. Page 1 of 19 American Journal of Medical Genetics: Part A
Green et al. Page | 1 1 2 3 De Novo SETD5 Loss-of-Function Variant as a Cause for Intellectual Disability 4 5 in a 10-year old boy with an Aberrant Blind Ending Bronchus 6 7 8 9 SETD5 10 Short Title: variant and blind ending bronchus 11 1 2 3 1 12 Green C , Willoughby J , DDD Study , Balasubramanian M 13 14 1Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, UK 15 16 2Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, 17 18 For Peer Review 19 UK 20 3 21 DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK 22 23 24 25 Correspondence to: 26 27 Dr Meena Balasubramanian 28 29 30 Sheffield Clinical Genetics Service 31 32 Sheffield Children's NHS Foundation Trust 33 34 Sheffield, UK 35 36 Ph: +44 114 2717025 37 38 39 Fax: +44 114 2737467 40 41 E mail: [email protected] 42 43 44 45 46 47
48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. American Journal of Medical Genetics: Part A Page 2 of 19
Green et al. Page | 2 1 2 3 ABSTRACT 4 5 Although rare, 3p microdeletion cases have been well described in the clinical 6 7 literature. The clinical phenotype includes; intellectual disability (ID), growth 8 9 10 retardation, facial dysmorphism and cardiac malformations. Advances in 11 12 chromosome microarray (CMA) testing narrowed the 3p25 critical region to a 124kb 13 14 region, and recent Whole Exome Sequencing (WES) studies have suggested that 15 16 the SETD5 gene contributes significantly to the 3p25 phenotype. Loss of Function 17 18 SETD5For Peer Review 19 (LoF) variants in are now considered a likely cause of ID. 20 21 We report here a patient with a frameshift LoF variant in exon 12 of SETD5. 22 23 This patient has features overlapping with other patients described with LoF SETD5 24 25 variants to include; similar facial morphology, feeding difficulties, intellectual 26 27 disability, behavioural abnormalities and leg length discrepancy. In addition, he 28 29 30 presents with an aberrant blind ending bronchus. 31 32 This report adds to publications describing intragenic mutations in SETD5 and 33 34 supports the assertion that de novo LoF mutations in SETD5 present with an 35 36 overlapping but distinct phenotype in comparison with 3p25 microdeletion 37 38 39 syndromes. 40 41 42 43 KEY WORDS 44 45 3p microdeletion, 3p25, SETD5, aberrant blind ending bronchus, intellectual 46 47 disability, loss of function. 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Page 3 of 19 American Journal of Medical Genetics: Part A
Green et al. Page | 3 1 2 3 INTRODUCTION 4 5 Intellectual Disability (ID) has a worldwide prevalence of approximately 1% 6 7 3% and has become the most frequent reason for referral to paediatric genetic 8 9 10 services [Maulik and Darmstadt 2007]. Due to its clinical and genetic heterogeneity, 11 12 the underlying cause for ID remains unclear. However, advances in genetic testing 13 14 have led to the elucidation of several novel genes linked to ID, some of the most 15 16 successful studies have led to the identification of de novo LoF sequence variants in 17 18 For Peer Review 19 candidate genes [de Ligt and others 2012; Rauch and others; Vissers and others 20 21 2010]. 22 23 Distal deletions of the short arm of chromosome 3 were first characterised by 24 25 cytogenetic and FISH analysis [Aqua and others 1995; Verjaal and De Nef 1978]. 26 27 This condition results in a well described syndrome associated with a clinical 28 29 30 phenotype that includes; intellectual disability, growth retardation, facial 31 32 dysmorphism and cardiac malformations. The severity of the condition varies 33 34 considerably, with the size of the deletion apparently correlating with the severity of 35 36 the phenotype [Drumheller and others 1996]. 37 38 39 A report by Kellogg and others [2013] described 4 patients with 3p25.3 40 41 deletions and ID, including 3 previously reported patients by Peltekova and others 42 43 [2012], Riess and others [2012] and Gunnarsson and Foyn Bruun [2010]. These 44 45 3p25.3 deletion carriers had a narrow range of overlap comprising of 3 genes 46 47 including SETD5. In addition to ID, patients had a common phenotype of depressed 48 49 50 nasal bridge (3/4), low set ears (3/4) and philtrum differences (3/4). Other features 51 52 were more variable including; cardiac malformations (2/4), ptosis (2/4), low birth 53 54 weight/growth retardation (2/4), seizures (2/4) and microcephaly (2/4) [Kellogg and 55 56 others 2013]. 57 58 59 60 John Wiley & Sons, Inc. American Journal of Medical Genetics: Part A Page 4 of 19
Green et al. Page | 4 1 2 3 Following this, 7 patients with independent LoF variants in SETD5 from a 4 5 cohort of 996 patients with moderate/severe ID (0.7% of cohort) were reported. 6 7 Features included; speech delay, behavioural problems and autism. Similar 8 9 10 dysmorphology i.e. brachycephaly, prominent forehead, abnormal eyebrows, similar 11 12 nose morphology (long, thin, tubular), eye morphology (long, narrow, upslanting 13 14 palpebral fissures, mild ptosis, unilateral amblyopia, nystagmus, strabismus) and 15 16 large, fleshy, low set ears were reported. Again, more variable features included; 17 18 For Peer Review 19 cardiac malformations (2/7), skeletal abnormalities (leg length discrepancy, scoliosis, 20 21 kyphosis, lordosis) and genitourinary abnormalities (4/7) [Grozeva and others 2014]. 22 23 Kuechler and others [2015] went on to expand the phenotype further and 24 25 described 4 unrelated patients with 4 different non recurrent microdeletions on 26 27 chromosome 3p25 narrowing down the smallest region of overlap to 94kb including 28 29 SETD5 30 only 2 coding genes, and parts of THUMPD3. Included in the cohort were 2 31 32 patients with intragenic SETD5 variants. Patients were compared with those from 33 34 Kellogg and others [2013], Peltekova and others [2012], Riess and others [2012] and 35 36 Gunnarsson and Foyn Bruun [2010]. Both microdeletion carriers and intragenic 37 38 SETD5 39 variant carriers had a similar craniofacial phenotype of striking eyebrows 40 41 (full, broad, straight, arched or with synophyrys), a tubular nose with broad nasal 42 43 bridge, bulbous nasal tip, anteverted nares, a long philtrum and downturned corners 44 45 of the mouth. Just like previous reports, features which showed incomplete 46 47 penetrance were cardiac malformations and postaxial polydactyly. 48 49 50 An emerging behavioural phenotype was supported with almost all the LoF 51 52 mutation carriers and 3 microdeletion carriers showing some behavioural problems. 53 54 Patients with larger deletions had additional facial differences (blepharophimosis, 55 56 abnormal slanting of palpebral fissures and ptosis). Microdeletion carriers were more 57 58 59 60 John Wiley & Sons, Inc. Page 5 of 19 American Journal of Medical Genetics: Part A
Green et al. Page | 5 1 2 3 likely to be of short stature, microcephalic and hypotonic and microdeletion carriers 4 5 also showed more severe speech impairment. 6 7 The only published cases of an inherited SETD5 variant suggested a more 8 9 10 variable phenotype. Two siblings with developmental delay and features consistent 11 12 with previously reported SETD5 de novo cases were compared to their father who 13 14 had only mild intellectual impairment with some features of SETD5. These patients 15 16 did not have ritualised behaviour or autism, abnormalities in eye structure, 17 18 For Peer Review 19 gastrointestinal and/or abdominal wall defects or scoliosis/kyphosis [Szczałuba and 20 21 others 2016]. 22 23 Frequency data for SETD5 mutations is difficult to obtain. However, the 24 25 genetic database Decipher includes 34 patients with SETD5 sequence variants 26 27 (https://decipher.sanger.ac.uk/), the SFARI database of genes linked with autism has 28 29 SETD5 30 47 mutations reported in its human gene module (https://sfari.org/) and a 31 32 recent large study of 4,293 patients recruited from the Deciphering Developmental 33 34 Disorders (DDD) study identified 17patients with de novo SETD5 mutations 35 36 [Deciphering Developmental Disorders 2017]. SETD5 is, therefore, likely one of the 37 38 39 most commonly mutated genes in developmental disorders [Deciphering 40 41 Developmental Disorders 2017]. 42 43 Adding to published reports, we present a patient with a de novo 44 45 heterozygous c.1381_1388del, p.(Asn461fs) frameshift mutation in exon 12 of 46 47 SETD5, who also has an aberrant blind ending bronchus, thus expanding the 48 49 50 phenotype. 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. American Journal of Medical Genetics: Part A Page 6 of 19
Green et al. Page | 6 1 2 3 MATERIALS AND METHODS 4 5 This patient was recruited to the Deciphering Developmental Disorders 6 7 (DDD) study. Trio based exome sequencing was performed on the affected 8 9 10 individual and their parents, as previously described [Wright and others 2014]. Each 11 12 affected individual also had a high resolution analysis for copy number abnormalities 13 14 using array based comparative genomic hybridization (aCGH). Putative de novo 15 16 mutations were identified from exome data using DeNovoGear software [Ramu and 17 18 For Peer Review 19 others 2013] and were validated using targeted Sanger sequencing. Mutation 20 21 nomenclature is according to HGVS guidelines with reference transcript 22 23 NM_001080517.2. 24 25 CLINICAL REPORT 26 27 This patient is the second child of healthy non consanguineous, White 28 29 30 European parents with unremarkable family history. He was born at term with a birth 31 32 weight of 2.976kg, following an uneventful pregnancy. Raised alpha fetoprotein 33 34 (AFP) levels were noted but antenatal scans were normal. There were no postnatal 35 36 complications. Failure to thrive and difficulty gaining weight were noted and he later 37 38 39 required fundoplication. He was born with postaxial polydactyly in all extremities 40 41 requiring surgical removal at the age of 4 months and tongue tie. Persistent cough 42 43 was noted at age 2 days and recurrent infections have continued to affect him, with a 44 45 later diagnosis of asthma. His chest infections were thought to be due to an aberrant 46 47 blind ending bronchus identified on bronchoscopy. There were no concerns with his 48 49 50 vision but conductive hearing loss was treated with grommet insertion. 51 52 Developmentally, at 10 months he could not sit unaided, he walked at 23 53 54 months. Leg asymmetry was detected subsequently. His first word was at 13 55 56 months, with a vocabulary of single words at 2 years. At a clinical psychologist 57 58 59 60 John Wiley & Sons, Inc. Page 7 of 19 American Journal of Medical Genetics: Part A
Green et al. Page | 7 1 2 3 assessment at 5 ½ years old, a Verbal IQ of 83 (13th percentile) and Performance 4 5 IQ of 98 (45th percentile) were recorded. Assessment also showed some weakness 6 7 in social communication and a stutter with recurrent dribbling. However, he did not 8 9 10 fulfil criteria for Autistic Spectrum Disorder. At age 7, he was attending mainstream 11 12 school with additional support. He was reported at school to have a dyslexic profile 13 14 with ‘low average’ level. In terms of behaviour, repetitive stereotyped behaviours 15 16 were noted such as repeatedly touching his face. He was late to develop imaginary 17 18 For Peer Review 19 play and weakness in social interaction with peers was noted. Reassessment at age 20 21 9 highlighted his complex communication needs and problems acquiring language 22 23 skills. 24 25 On examination age 2 ½, he was noted to have brachycephaly with 26 27 prominence in forehead, metopic ridge, hypertelorism, clinodactyly and prominent 28 29 30 left ear (Figure 1 which shows evolving facial dysmorphism with age). Left leg was 2 31 32 cms longer than right with a small café au lait mark (0.5cm) on left leg. Height was 33 34 89cm (25th centile), weight was 13.11kg (25th centile), and head circumference was 35 36 49cm (2nd 9th centile). 37 38 39 Investigations included metabolic tests; urine organic acids and amino acids, 40 41 creatine kinase, alpha feta protein, thyroid function, mucopolysaccharides were 42 43 normal. Echocardiogram and renal ultrasound were also reported normal. 44 45 Cytogenetics showed a normal male karyotype (46,XY) and FISH testing for deletion 46 47 or duplication of the TBX1 locus at 22q11.2 was negative. Testing for primary ciliary 48 49 50 dyskinesia was also normal along with normal ophthalmology assessment which 51 52 included electroretinogram. Panel genetic testing for Bardet Biedl Syndrome was 53 54 normal. Patient was enrolled in the Deciphering Developmental Delay (DDD) 55 56 57 58 59 60 John Wiley & Sons, Inc. American Journal of Medical Genetics: Part A Page 8 of 19
Green et al. Page | 8 1 2 3 [DECIPHER ID: 259090] study which identified a de novo heterozygous 4 5 c.1381_1388del, p.(Asn461fs) frameshift mutation in exon 12 of SETD5. 6 7 DISCUSSION 8 9 10 The 3p critical region was initially thought to be a 3 5Mb region [Aqua and 11 12 others 1995]. Subsequent patients were described with a narrow region of 13 14 overlapping regions [Gunnarsson and Foyn Bruun 2010; Kellogg and others 2013; 15 16 Peltekova and others 2012; Riess and others 2012] and SETD5 was considered to 17 18 For Peer Review 19 be the strongest candidate gene [Peltekova and others 2012; Shuib and others 20 21 2009]. Further evidence to support pathogenicity of SETD5, came from large cohorts 22 23 of de novo mutation carriers [Iossifov and others 2014; Pinto and others 2016; 24 25 Rauch and others 2012; Deciphering Developmental Disorders 2017]. 26 27 The coding sequence of SETD5 is 4329bp long and encodes 1442 amino 28 29 30 acids. It is ubiquitously expressed and high levels have been seen in the cerebral 31 32 cortex, the intestine and the eye [Kuechler and others 2015; Nagase and others 33 34 1997]. The gene is highly evolutionarily conserved suggesting that it is functionally 35 36 important and is considered a member of the ‘writers’ group of epigenetic genes 37 38 39 [Kleefstra and others 2006]. 40 41 In silico domain analysis has showed that SETD5 is a multidomain protein 42 43 containing a SET domain and a putative PHD domain [Kuechler and others 2015]. It 44 45 thought have an important role in cell replication and gene expression through 46 47 regulation of histone acetylation [Hu and others 2010; Jones and others 2008; 48 49 50 Tanaka and others 2000; Yao and others 1998]. Genes encoding histone modifiers 51 52 are increasingly recognised to have a contribution to ID [Berdasco and Esteller 53 54 2013]. 55 56 57 58 59 60 John Wiley & Sons, Inc. Page 9 of 19 American Journal of Medical Genetics: Part A
Green et al. Page | 9 1 2 3 Animal models have demonstrated that SETD5 is important in mammalian 4 5 development with SETD5 deficient mouse embryos exhibiting severe developmental 6 7 delay, vascular abnormalities, apoptosis, and reduced cellular proliferation; findings 8 9 10 consistent with impairment of gene expression [Osipovich and others 2016]. 11 12 Histone modifier genes are all dosage sensitive and haploinsufficiency is 13 14 believed to be the disease mechanism. In vitro analysis has shown that variants in 15 16 SETD5 trigger nonsense mediated decay (NMD) pointing to LoF [Kuechler and 17 18 For Peer Review 19 others 2015]. Haploinsufficiency of a single gene has also proven to be casual for 20 21 the specific phenotype in a number of microdeletion syndromes. There are several 22 23 examples of this including; EHMT1 in association with 9q34 deletion and SATB2 in 24 25 association with 2q33.1 deletion. 26 27 The phenotypic features of our patient with a de novo SETD5 variant fit with 28 29 30 previously described patients to include; ID, language delay, ritualised behaviour, 31 32 feeding difficulties, abnormal ears, eyebrows, shape of nose and polydactyly (see 33 34 Table I). Common features described in the literature that our patient did not have 35 36 include; micrognathia (8/13), thin upper lip (8/13), gastrointestinal defects (5/13) and 37 38 39 genitourinary defects (6/13). 40 41 The observation of brachycephaly was made only in our patient and 3 patients 42 43 in the Grozeva and others [2014] cohort (3/7). Unsteady gait and hypertelorism are 44 45 only described in our patient and 1 of the patients in the Szczałuba and others [2016] 46 47 paper. 48 49 50 Congenital heart defects appear to be more of a feature of the microdeletion 51 52 syndrome [Gunnarsson and Foyn Bruun 2010; Peltekova and others 2012] with only 53 54 4/13 patients in the SETD5 group affected. Knockout mice models have shown that 55 56 SETD5 may be important for embryonic stem cells to differentiate into 57 58 59 60 John Wiley & Sons, Inc. American Journal of Medical Genetics: Part A Page 10 of 19
Green et al. Page | 10 1 2 3 cardiomyocytes [Osipovich and others 2016] and given the nature of cardiac 4 5 anomalies reported in the literature, it is reasonable to consider a cardiac 6 7 assessment at the time of initial diagnosis. 8 9 10 Behavioural problems including obsessive compulsive disorder (OCD) and 11 12 autism were common findings (6/13). Most of the patients with SETD5 pathogenic 13 14 variants have truncating variants (frameshift or nonsense variants) and whilst some 15 16 de novo missense variants have been reported in large cohorts of autism patients as 17 18 For Peer Review 19 being causative, extended phenotypic descriptions are not available to assign 20 21 causality (Table I). Based on data presented by [Li and others 2016; Neale and 22 23 others 2012] there is insufficient evidence to link the reported SETD5 missense 24 25 variants with autism or susceptibility to autism. Our patient had been assessed for 26 27 autism but did not meet criteria for a diagnosis. He did show signs of ritualised 28 29 30 behaviour with some areas of weakness in social communication. This is 31 32 increasingly being observed in children with underlying genetic conditions 33 34 contributing to their behaviour profile i.e. their behavioural problems are not typical 35 36 and hence, will not fulfil the diagnostic criteria for autism spectrum disorder. 37 38 39 However, it is well–recognised that their learning needs and behavioural traits can be 40 41 challenging to manage and needs appropriate assessment to tailor resources to their 42 43 needs. 44 45 The notable difference in our patient is the presence of a blind ending 46 47 bronchus. Although recent studies have highlighted the integral role of SETD5 in 48 49 50 mammalian development, it remains unclear if the blind ending bronchus is related to 51 52 the SETD5 mutation or whether it has an independent cause. 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Page 11 of 19 American Journal of Medical Genetics: Part A
Green et al. Page | 11 1 2 3 CONCLUSION 4 5 We report a 10 year old boy with a de novo LoF variant in SETD5 and provide 6 7 a comprehensive review of published literature on this frequently reported ID gene. 8 9 10 The emerging phenotype includes; ID, facial dysmorphology, skeletal anomalies, 11 12 behavioural problems and speech and language difficulties. We report for the first 13 14 time, aberrant blind ending bronchus as a possible association with this phenotype. 15 16 Further case reports of this nature are required to expand the phenotype and 17 18 For PeerSETD5 Review 19 understand variable expressivity of especially as genomic sequencing 20 21 studies identify variants of interest in this gene. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. American Journal of Medical Genetics: Part A Page 12 of 19
Green et al. Page | 12 1 2 3 FIGURE AND TABLE LEGENDS 4 5 6 Figure 1: Facial dysmorphism of this patient evolving with age demonstrating 7 8 prominent forehead, upslanting palpebral fissures, bilateral low set, posteriorly 9 10 rotated ears, smooth philtrum. 11 12 13 Table I: Clinical features of patients with de novo SETD5 variants in comparison to 14 15 our patient. 16 17 ACKNOWLEDGEMENTS 18 For Peer Review 19 The DDD study presents independent research commissioned by the Health 20 21 22 Innovation Challenge Fund [grant number HICF 1009 003], a parallel funding 23 24 partnership between the Wellcome Trust and the Department of Health, and the 25 26 Wellcome Trust Sanger Institute [grant number WT098051]. The views expressed in 27 28 this publication are those of the author(s) and not necessarily those of the Wellcome 29 30 Trust or the Department of Health. The study has UK Research Ethics Committee 31 32 33 approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 34 35 granted by the Republic of Ireland REC). The research team acknowledges the 36 37 support of the National Institute for Health Research, through the Comprehensive 38 39 Clinical Research Network. 40 41 42 43 44 We would also like to thank the family for consenting to this publication. 45 46 47 48 CONFLICTS OF INTERESTS 49 50 51 None to declare 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Page 13 of 19 American Journal of Medical Genetics: Part A
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Figure 1: Facial dysmorphism of this patient evolving with age demonstrating prominent forehead, 33 upslanting palpebral fissures, bilateral low-set, posteriorly rotated ears, smooth philtrum. 34 35 254x190mm (96 x 96 DPI) 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. American Journal of Medical Genetics: Part A Page 18 of 19
1 2 Table I: Clinical features of patients with de novo SETD5 variants in comparison to our patient 3 4
Grozeva et Grozeva et Grozeva et Grozeva et Grozeva et Grozeva et Grozeva et Kuechler et Kuechler et Szczaluba et Szczaluba et Szczaluba et 5 Our patient al.2013 al.2013 al.2013 al.2013 al.2013 al.2013 al.2013 al.2015 al.2015 al.2016 al.2016 al.2016 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 1 Patient 2 6 Proband Brother Father 7 Chr3:9477570 Chr3:9486924- Chr3:9490142 Chr3:95172 Chr3:951730 8 Chr3:9486 _9477650del Chr3:9490270 Chr3:0095123 Chr3:009512 Chr3:0095123 9486932 Chr3:9486739 Chr3:9489453 c.2177_2178d Chr3:9512419 16 2 877 c.547_567+60 C>T 36C>G;_00108 336C>G;_001 36C>G;_0010 9 Mutation c.1381_1388 del c.1195A>T c.1866C>G el c.3001C>T c.3771dup c.3846del c.1333C>T del c.2302C>T 0517.2. 080517.2. 80517.2. p.Asn461Profs*1 p.Lys399** p.Tyr622** p.Thr726Asnf p.Arg1001* p.Ser1258G p.Ser1286Le 10 p.Arg445* p.Pro183_Lys p.Arg768* Ser973* Ser973* Ser973* 5 s*39 lufs*65 aufs*84 11 189del 12 Gender M M M M M M M M F F M M M 13 Descent Caucasian NR NR For NR Peer NR NR Review NR NR Caucasian Caucasian NR NR NR 14 Age (years) at last 6 5/12 NR NR NR NR NR NR NR 20 9 10/12 42/12 12 2/12 31 15 examination 109.7cm 96cm 78cm 170cm 16 50-75th 178cm 134cm Height 2nd centile NR 2nd centile NR 25-50th centile NR NR -2.1SD 0SD -0.8SD centile 2.26 SD -1.18 SD 17 Below 3rd 50th 10th-25th 18 18.05kg 14kg 5kg 64kg th th th 67kg 28.5kg Weight 9 centile NR NR 9 centile NR 25-50 centile NR NR 1.5SD -5.4SD -0.4SD
19 3rd centile Below 3rd 25th-50th 51cm 47.5cm 56cm 20 51.5cm 75-98th 58cm 50.5cm OFC 25th centile 50-75th centile 10-25th centile 75-91st centile 75th centile 10th centile -0.3SD -0.2SD -0.5SD 9th centile centile 2.46 (SD) -1.26 (SD) 21 25th-50th 25th-50th 25th 22 Uneventful Raised AFP NR NR NR NR NR NR NR + + NR NR NR 23 Pregnancy Normal scans
24 Gestation term 34/40 38/40 term term 35.5/40 term term 40/40 40/40 41/40 36/40 NR 25 2.97 2.35 Birth Weight 2.92 2.47 2.69 2.99 3.66 2.41 2.95 small 3.20 3.07 -1SD 2.1SD NR 26 (kg) 9th centile 15th 1st-3rd 27 Y- chewing Y œ Feeding Y œ chewing and 28 Y - reflux Y swallowing N N N NR NR Y Y NR Difficulties difficulties swallowing difficulties 29 difficulties
30 Dribbling Y N N N N Y Y Y NR NR NR NR NR 31 Prominent left ear Large ears Large ears Low Fleshy ear Long,narrow Bilateral ear 32 Ears Posteriorly rotated Periauricular Long,narrow NR Fleshy ear lobes NR NR set/malformed Y lobes low set ears N creases 33 bilateral low set pit low set ears ears Nystagmus Long narrow Long narrow Strabismus 34 and fissures Upslanting fissures Upslanting Down slanting Mildly down Left eye strabismus Mild ptosis Myopia/astigm 35 Eyes Hypertelorism palpebral Upslanting palpebral palpebral slanting Hypertelorism N amblyopia Upslanting Upslanting atism N fissures palpebral fissures fissures palpebral 36 palpebral palpebral fissures fissures 37 fissures fissures Synophrys Synophrys Pencilled fine Full 38 Eye brows Straight Synophrys NR Cyst in eyebrows NR Broad NR NR N N eyebrows eyebrows N 39 eyebrows eyebrows Broad Broad bridge 40 bridge, Prominent Bulbous tip Broad bridge, Broad bridge, Depressed Tubular nose Bulbous tip high nasal root Prominent Anteverted Depressed Prominent Bulbous tip bulbous tip nasal bridge 41 Abnormally Nose Prominent nasal Tubular nose Anteverted Tubular nose high nasal root nares nasal bridge high nasal Anteverted Anteverted Abnormally Abnormally shaped 42 root nares Prominent Tubular nose Depressed nasal root nares nares shaped shaped 43 Depressed nares bridge Long philtrum Short nose nasal Prominent high 44 45 46 John Wiley & Sons, Inc. 47 48 49 Page 19 of 19 American Journal of Medical Genetics: Part A
1 2 bridge nasal root 3 Tubular nose
4 Long Short philtrum Long philtrum Long philtrum Long philtrum Long philtrum Small mouth philtrum Small mouth Small mouth Open mouth Long philtrum 5 Mouth/ Lower Micrognathia Long philtrum Long philtrum Downturned Downturned Long philtrum Short Philtrum Thin upper Long philtrum NR Micrognathia with an everted Thin upper lip face Thin upper lip Thin upper lip Thin upper lip corners of the corners of the Micrognathia 6 lip Micrognathia Thin upper lip full lower lip Micrognathia High palate mouth mouth 7 High palate Micrognathia 8 Cleft palate Crowded Crowded Crowded Teeth NR NR NR NR NR NR NR NR NR NR 9 teeth teeth teeth 10 Post axial Prominent polydactyly 11 Post axial finger joints post axial Long and thin Post axial Single Digits polydactyly NR NR Clinodactyly NR NR NR Broad distal N polydactyly fingers polydactyly transverse 12 Clinodactyly phalanges palmar 13 Sandal gaps For Peer Review creases 14 Leg length Leg length Leg length discrepanc Lordosis Sacral dimple Pectus 15 Skeletal discrepancy discrepancy y Scoliosis Lordosis NR Stiff legged NR NR NR N N Stiff legged gait Excavatum 16 Unusual gait Scoliosis Sacral gait dimple 17 Brachycephaly Cranio-facial Prominent Brachycephal Brachycep Prominent Brachycephal Triangular 18 NR NR NR NR NR Triangular face Triangular face features forehead y haly forehead y face 19 Metopic ridge 1 febrile 20 Hypotonic Neurology NR NR NR NR NR NR NR NR seizure at 8 NR Hypotonic N Unsteady gait 21 years Bilateral 22 Inguinal Paraumbilical Inguinal bilateral vesico- Abnormal cryptoorchism Blind ended hernia hernia hernia ureteral reflux 23 organ Hypospadias Hypospadias NR NR NR NR bilateral N bronchus Undescend Undescended Nocturnal with posterior development vesico- 24 ed testes testes enuresis urethral valve ureteral reflux 25 ASD,PDA, persistent left 26 Heart NR VSD,PDA MVP NR NR NR NR NR NR NR ASD N superior vena 27 cava Development 28 Y Y Y Y Y Y Y Y Y Y Y Severe Y - Mild ID 29 al Delay 30 Walking (age) 19-23 months 24 months 36 months 18 months NR 24 months 38 months 20 months 24-36 months 20 months 18 months NR NR 31 Speaking 32 (age at first 13 months 4 years 4 years 12 months Late 18 months 2 years NR 4 years 4 years 4 years NA NR words) 33 Stammer Motor dyspraxia Speech Expressive Expressive Severe delay- 34 Speech Expressive dysfluency NR Stammer Stammer NR language language NR NR only a few NR N problems language delay 35 Expressive delay delay words at 4 language delay 36 Repetitive Dominant in Repetitive Repetitive Repetitive stereotyped know, anxious 37 Behaviour stereotyped stereotyped NR NR stereotyped Autistic OCD OCD Mild ADD N N N activities in unknown activities activities activities 38 Autistic OCD situations 39 Recurrent Recurrent Other NR NR NR NR NR NR NR NR NR Exophthalmos NR 40 infections infections Mutation nomenclature according to HGVS guidelines ( http://varnomen.hgvs.org /), using NCBI reference transcript NM_001080517.2. 41 Abbreviations: NR=Not Recorded, M=Male, F=Female, Y=Yes, N=No, SD=Standard Deviations, AFP=Alpha FetoProtein, ASD= Artrioventricular Septal Defect VSD=Ventricular Septal Defect, PDA=Patent Ductus Arteriosus, MVP=Mitral valve prolapse, 42 OCD=Obsessive Compulsive Disorder, ADD=Attention Deficit Disorder, ID = Intellectual Disability 43 44 45 46 John Wiley & Sons, Inc. 47 48 49