Genetic diagnosis of congenital hypopituitarism by Molecular Inversion Probes Sequencing: novel pathogenic variants

CAMILLETI, MARÍA ANDREA; MERCOGLIANO, MARÍA FLORENCIA; VISHNOPOLKA, SEBASTIÁN; BRAVSLAVSKY, DEBORA; KESELMAN, ANA; BERGADÁ, IGNACIO; MARINO, ROXANA; RAMÍREZ, PABLO; PÉREZ GARRIDO, NORA; CIACCIO, MARTA; DI PALMA, MARÍA ISABEL; BELGOROSKY, ALICIA; MARTÍ, MARCELO; KITZMAN, JACOB; CAMPER, SALLY; PÉREZ MILLÁN, MARÍA INÉS

Mar del Plata

Congreso; LXIV Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

Sociedad Argentina de Investigación Clínica (SAIC)

Congenital hypopituitarism (CH) is a life-long and threatening disease, associated with an abnormalpituitary development. CH is highly variable comprising aspectrum of disorders that range from isolated growth hormonedeficiency (IGHD) to combined pituitary hormone deficiency(CPHD). Mutations in at least 30 genes have been implicated inCH, but at present, precise diagnosis remains a challenge. In thepresent study, we report variants found in pediatric patients withCPHD (n= 116) or IGHD (n= 55) from Argentina using themolecular inversion probes sequencing (MIPS) method and ourown custom designed gene panel. We identified pathogenic,likely pathogenic or variants with uncertain significance butpredicated to be damaging for at least 3 independent software inabout 23 % of the cases. We have identified a number ofphenotypes associated with mutations in known genes that causehypopituitarism (HESX1, LHX3, LHX4, GLI2); in less frequentlyreported genes (BMP4, FGFR1, GLI3, TGIF1, FOXA2) and ingenes that require additional evidence about causality (ARNT2,ZSWIM6, GPR161, PNPLA6, CDH2). We have identified de novoheterozygous variants in LHX3 and LHX4, transcription factorsinvolved in the development of the pituitary. Two variants onLHX3 (p.L220S and p.P187S) were found in a patient with IGHDand a patient with CPHD, micrognathia, chiasm hypoplasia andbilateral cryptorchidism. LHX4 variants (p.Q100H, p.W204L and p.R84H) were found in a child with septo optic dysplasia, a childwith CPHD and a third patient with GH and TSH deficiency,respectively. Transient transfection of HEK293T cells with humanwild-type or mutant hLHX3/ hLHX4 showed an impairment intranscriptional reporter activity by the mutant variants, exceptfor variant LHX4 p.R84H. Collectively, using the first screeningpanel for known genes and candidate genes for CH, we identifieda significant number of variants in a large cohort of patientsassociated with the complex phenotype. Our studies will facilitateearly diagnosis and prognosis, assessing the risk of futureaffected individuals. Furthermore, understanding themechanisms behind new genes involved in CH would lead us todevelop new tailor-made therapies that could benefit thepatients.