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 1.116.5) 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 18 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.
|Patient||Age (years)||Height SDS||Clinical details||CNV||CNV Class||NH-CSS criteria|
|1||12.8||−3.6||iangular face, high arched palate, feeding difficulties.||1q21 del||4||2/6|
|2||10.1||−1.6||Feeding difficulties, dyslexia.||1q21 del||4||2/6|
|3||9.1||−3.7||Clinodactly, feeding difficulties.||1q21 del||4||3/6|
|4||11.3||−5.1||Triangular face, long lashes||12q14 del||5||2/6|
|5||1.9||−5.7||Low set ears, triangular face, delayed motor development||7q21 del, 7q31 del, 7q31 del||4,3,5||2/6|
|6||14.4||−2.7||No dysmorphic features||7q21 dup, Xp22 dup||3,3||2/6|
|7||2.8||−4.9||Triangular face, frontal bossing, feeding difficulties||15q11 del||4||3/6|
|8||2.7||−2.0||Adrenal insufficiency||7q36 dup||3||2/6|
|9||17||−4.0||Learning difficulties, delayed puberty||5q12 del||3||1/6|
|10||2.5||−3.6||Short limbs||3p22 del, 15q13 dup||3,4||1/6|
|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.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology