ESPE Abstracts (2018) 89 RFC4.3

A Deletion Encompassing Exon 2 of the ALS Gene: Analysis of a Patient with ALS Deficiency and His Family

Helena Poggia, Monica Arancibiab,c, Felipe Benavidesd, Carlos Lagose, Andrea Vecchiolae, Gonzalo Dominguez-Menendeza & Alejandro Martinez-Aguayoa


aEndocrinology Unit, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; bServicio de Pediatria, Hospital Higueras, Talcahuano, Chile; cEndocrinology Unit, Pediatrics Division, Pontificia Universidad Catolica de Chile, Santiago, Chile; dFacultad de Medicina, Genetics and Genomics Center, Universidad del Desarrollo y Clínica Alemana, Santiago, Chile; eEndocrinology Department, Pontificia Universidad Católica de Chile, Santiago, Chile


The main role of the acid-labile subunit (ALS) is to stabilize the IGFBP3/IGF complexes. Pathogenic variants in the gene coding for ALS (IGFALS) results in IGF1 and IGFBP3 deficiency, short stature, delay puberty and insulin resistance. The aim of these study was to identify the genetic cause in a patient with suspected ALS deficiency. The proband is the third son of non-consanguineous parents, evaluated for the first time at 17.3 years due to short stature (−2.84 S.D.) and delayed puberty (Tanner 2) and a bone age of 16 years. He showed IGF1 basal concentrations of 45 ng/ml (reference range: 193–731 ng/ml) and undetectable IGFBP3. GH concentrations after Clonidin test suggested GH insensitivity (11.2-19.3-10.7-7.25 ng/ml). No increases in IGF1 and IGFBP3 concentrations were found after 2 weeks of GH administration (0.1 and 0.2 U/kg per d). Neither the parents nor the four siblings had abnormal IGF1 or IGFBP3 concentrations. Since the findings in the proband suggested ALS deficiency, but ALS measurement was not available, Sanger sequencing of IGFALS was performed in the patient and his family. An apparently homozygous missense variant (c.1871C>T, p.Pro624Leu; NP_001139478.1) in exon 2 was found in the index case and on one allele in his father. This missense variant has been reported by the Exome Aggregation Consortium in only 1 allele among 44,672 individuals, but not in a clinical context. In silico analysis with PolyPhen-2 predicts that it is probably damaging with a high score. Since this point mutations was not found in the mother, MLPA analysis of the IGFALS gene was performed. The index case, as well as his mother and siblings, and not the father, showed a deletion encompassing at least a major part of exon 2, on one of their alleles.

Conclusion: To our knowledge, these is the first report of a large deletion in the IGFALS gene. The patient was the only one in his family with two affected alleles (p.[Pro624Leu];[deletion]) which is consistent with the phenotype. Identification of pathogenic variants in IGFALS is a useful tool to confirm the diagnosis of ALS deficiency as a probable cause of growth retardation in children with low IGF1 and very low IGFBP3. We suggest deletion/duplication analysis should be considered in the genetic analysis of ALS deficiency.

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