Biallelic SH2B3 germline variants are associated with a neonatal myeloproliferative disease and multisystemic involvement

Abstract

Known genetic disorders, such as Noonan syndrome and Down syndrome, can present in the neonatal period or early infancy with myeloproliferative disease (MPD) or abnormal myelopoiesis, which often self-resolves. This phenomenon results from an imbalance in differentiation and cell regulation caused by the genetic condition during perinatal hematopoiesis. Recently, SH2B3 variants have also been associated with neonatal MPD. However, data on their clinical significance, particularly across the spectrum of extra-hematological manifestations, of SH2B3 variants remain limited. Here, we describe the clinical features of ten children with SH2B3-associated disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in eight patients and in two patients from monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. Patients displayed a MPD in the first weeks of life, which was mostly self-limiting. Following the normalization of blood counts, thrombocytosis developed during childhood. Moreover, they presented with a multisystemic clinical features consisting in delayed growth, variable neurological impairment, autoimmune disorders. These data contribute to the definition of a clinical phenotype associated with germline biallelic SH2B3 LoF variants presenting with neonatal MPD, with important implications for patient management and follow-up.

Fig. 1. Genetic and structural characterization of SH2B3 germline variants in the study cohort.

A The upper section shows the distribution of SH2B3 variants in the study cohort on the SH2B3 protein. Mutations in bold have not been previously reported. The lower section presents published SH2B3 germline variants. PH: Pleckstrin homology domain; Phe-ZIP: Phenylalanine zipper; SH2: SH2 domain. #Mutation in trans on IGV variant viewer. B Location of Arg392, Glu395, Glu400, and Leu438 within the SH2 domain of SH2B3. The panel shows the SH2 domain (pink) complexed with the JAK2 peptide containing pTyr813 (light blue) (PBD: 7r8w). Three residues (Arg392, Glu395, and Glu400) are located close to pTyr813 and their non-conservative substitutions are predicted to perturb the intermolecular binding network stabilizing the SH2B3-JAK2 interaction (left). The mutated residues are highlighted in yellow with their lateral chains. The lateral chain of Leu438 is placed in a buried pocked formed by several hydrophobic residues (Trp364, Phe389, Val391, Leu402, Val434, Val435, Met437, Leu458; lateral chains showed in green). The Leu-to-Arg substitution introduces a positively charged lateral chain that is expected to dramatically perturb the conformational organization of the region, likely resulting in an aberrant folding of the entire SH2 domain (right). Both events are predicted to result in a defective function of the SH2 domain, causingAQ9 impaired binding of SH2B3 to JAK, and failure to functionally downmodulate the kinase. C Pedigrees for seven patients. Individual with a homozygous mutation or compound heterozygous or with a homozygous mutation on hematopoietic stem cells in each family are marked with arrows. Double line indicates consanguinity, which is present in three families. MPD myeloproliferative disorder; NA not assessed; wt wild-type; * SH2B3 variant.

Fig. 2. Peripheral blood and bone marrow findings in patients with SH2B3 germline variants.

Peripheral blood A, C and BM aspirate B, D of P8.1 A, B and P9.1 C, D: Anisopoikilocytosis of red blood cells with teardrops, increased platelets with anisocytosis and giant platelets A Enlarged megakaryocyte with abundant cytoplasm and hyperlobulated nucleus B. Myelocyte and atypical monocytes. C Hyperplastic and left shifted myelopoiesis D. BM biopsy of patient P1.1 E–H: Hypercellular BM E, H, E with clusters of atypical, enlarged megakaryocytes (F, (H, E; 4x magnification of E). Increased granulopoiesis (G; MPO immunohistochemistry) and reduced and left shifted erythropoiesis (H; CD71 immunohistochemistry).