The genetic landscape of children born small for gestational age with persistent short stature (SGA-SS)

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F24%3A10459215" target="_blank" >RIV/00216208:11130/24:10459215 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064203:_____/24:10459215

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Xssh4xsh7m" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Xssh4xsh7m</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1159/000530521" target="_blank" >10.1159/000530521</a>

Jazyk výsledku

angličtina

Název v původním jazyce

The genetic landscape of children born small for gestational age with persistent short stature (SGA-SS)

Popis výsledku v původním jazyce

Introduction. Among children born small for gestational age, 10-15% fails to catch-up and remains short (SGA-SS). The underlying mechanisms are mostly unknown. We aim to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. Methods.Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight &lt;-2 SD for gestational age, and life-minimum height &lt;-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. Results. The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic gene variants (P/LP) affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%) we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children.Conclusions. The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role of the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and from intracellular regulation and signalling.

Název v anglickém jazyce

The genetic landscape of children born small for gestational age with persistent short stature (SGA-SS)

Popis výsledku anglicky

Introduction. Among children born small for gestational age, 10-15% fails to catch-up and remains short (SGA-SS). The underlying mechanisms are mostly unknown. We aim to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. Methods.Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight &lt;-2 SD for gestational age, and life-minimum height &lt;-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. Results. The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic gene variants (P/LP) affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%) we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children.Conclusions. The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role of the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and from intracellular regulation and signalling.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30202 - Endocrinology and metabolism (including diabetes, hormones)

Projekt

<a href="/cs/project/NV18-07-00283" target="_blank" >NV18-07-00283: Studium etiopatogeneze a optimalizace léčby u dětí s intrauterinní růstovou restrikcí a postnatálně přetrvávajícím selháním růstu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Hormone Research in Paediatrics

ISSN

1663-2818

e-ISSN

1663-2826

Svazek periodika

97

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

13

Strana od-do

40-52

Kód UT WoS článku

000963756200001

EID výsledku v databázi Scopus

2-s2.0-85184280511