ESPE Abstracts (2018) 89 RFC10.1

aWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University London, London, UK; bUCL Institute of Child Health, London, UK; cUniversity Hospitals of Leicester NHS Trust, Leicester, UK; dSheffield Children’s Hospital, Sheffield, UK; eMedical University of Bialystok, Bialystok, Poland; fAl Mafraq Hospital, Abu Dhabi, UAE; gMubarak Al-kabeer Hospital, Jabriya, Kuwait; hBirmingham Heartlands Hospital, Birmingham, UK; iRoyal Hospital for Children, Glasgow, UK; jGuy’s and St Thomas’ NHS Foundation Trust, London, UK; kViapath, Guy’s Hospital, London, UK

Introduction: Our Centre is an international referral centre for genetic analysis of children with short stature (SS) and features of GH/IGF-1 resistance. Following candidate gene and whole exome sequencing, diagnoses for ~50% patients remained elusive. Copy number variation (CNV) has not previously been investigated in GH/IGF-1 resistance and we hypothesised that CNVs contribute to the phenotype in our undiagnosed cohort.

Experimental Design and Methodology: CGH was performed with oligonucleotide array using ~60,000 probes in 60 patients (38M, mean age 7.0 years, range 1.1–16.5) mean height SDS −3.87 (range −1.58 to −7.44).

Results: We identified CNVs in 10/60 (17%) patients (Table 1), mean height SDS −3.7 (range −1.6 to −5.7). Interestingly, patients 1–8 had features of Silver Russell Syndrome (SRS). Due to clinical suspicion of SRS, patients 1, 5 and 7 had undergone SRS testing (11p15LOM and UPD(7)mat) which were negative.

Table 1 Copy Number Variants identified in our patients
PatientAge (years)Height SDSClinical detailsCNVCNV ClassNH-CSS criteria
112.8−3.6iangular face, high arched palate, feeding difficulties.1q21 del42/6
210.1−1.6Feeding difficulties, dyslexia.1q21 del42/6
39.1−3.7Clinodactly, feeding difficulties.1q21 del43/6
411.3−5.1Triangular face, long lashes12q14 del52/6
51.9−5.7Low set ears, triangular face, delayed motor development7q21 del, 7q31 del, 7q31 del4,3,52/6
614.4−2.7No dysmorphic features7q21 dup, Xp22 dup 3,32/6
72.8−4.9Triangular face, frontal bossing, feeding difficulties15q11 del43/6
82.7−2.0Adrenal insufficiency7q36 dup32/6
917−4.0Learning difficulties, delayed puberty5q12 del31/6
102.5−3.6Short limbs3p22 del, 15q13 dup3,41/6
Classification 3= Variant uncertain pathogenicity, 4= Likely pathogenic, 5= Predicted pathogenic. NH-CSS, Netchine-Harbison SRS Clinical Scoring System (3/6 plus recognised genetic change or 4/6 clinical features alone recommended for SRS diagnosis).

Conclusion: Our patient cohort was enriched for low frequency CNVs. 8/10 of these patients had features of SRS. Consistent with previous reports, the SRS phenotype in our patients with CNVs appears milder than classic cases due to 11p15LOM or UPD(7)mat. Our study is the first to report CNVs in patients with GH/IGF-1 resistance and contributes to the emerging SRS-like phenotype. Our findings emphasise the importance of CNV testing in SS patients, especially those with SRS features.

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