Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund-Thomson (RTS), RAPADILINO and Baller-Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390 þ 2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data.

Preterm birth is the major cause of neonatal mortality and morbidity. In many cases, it has severe life-long consequences for the health and neurological development of the newborn child. More than 50% of all preterm births are spontaneous, and currently there is no effective prevention. Several studies suggest that genetic factors play a role in spontaneous preterm birth (SPTB). However, its genetic background is insufficiently characterized. The aim of the present study was to perform a linkage analysis of X chromosomal markers in SPTB in large northern Finnish families with recurrent SPTBs. We found a significant linkage signal (HLOD  = 3.72) on chromosome locus Xq13.1 when the studied phenotype was being born preterm. There were no significant linkage signals when the studied phenotype was giving preterm deliveries. Two functional candidate genes, those encoding the androgen receptor (AR) and the interleukin-2 receptor gamma subunit (IL2RG), located near this locus were analyzed as candidates for SPTB in subsequent case-control association analyses. Nine single-nucleotide polymorphisms (SNPs) within these genes and an AR exon-1 CAG repeat, which was previously demonstrated to be functionally significant, were analyzed in mothers with preterm delivery (n = 272) and their offspring (n = 269), and in mothers with exclusively term deliveries (n = 201) and their offspring (n = 199), all originating from northern Finland. A replication study population consisting of individuals born preterm (n = 111) and term (n = 197) from southern Finland was also analyzed. Long AR CAG repeats (≥26) were overrepresented and short repeats (≤19) underrepresented in individuals born preterm compared to those born at term. Thus, our linkage and association results emphasize the role of the fetal genome in genetic predisposition to SPTB and implicate AR as a potential novel fetal susceptibility gene for SPTB.

Background: Preterm birth accounts for 2-3 million annual deaths worldwide and is the major cause of acute and chronic morbidity in children. More than 50% of preterm births have a spontaneous onset. Family studies suggest that genetic factors affect the risk of spontaneous preterm birth (SPTB). However, the genetic background is poorly known.