A biallelic mutation in encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis.

Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis.

Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis.

DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS.

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.

The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection.

The fibroblast growth factor receptor 2 p.Ala172Phe mutation in Pfeiffer syndrome--history repeating itself.

Pfeiffer syndrome is an autosomal dominant condition classically combining craniosynostosis with digital anomalies of the hands and feet. The majority of cases are caused by heterozygous mutations in the third immunoglobulin-like domain (IgIII) of FGFR2, whilst a small number of cases can be attributed to mutations outside this region of the protein. A mild form of Pfeiffer syndrome can rarely be caused by a specific mutation in FGFR1.

Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.

Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS.

Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily.

Apert syndrome (AS) is a severe disorder, characterized by craniosynostosis and complex syndactyly of the hands and feet. Two heterozygous gain-of-function substitutions (Ser252Trp and Pro253Arg) in exon IIIa of fibroblast growth factor receptor 2 (FGFR2) are responsible for >98% of cases. Here we describe two novel mutations in FGFR2 in the two patients in whom a mutation had not previously been found in our cohort of 227 AS cases.

A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb.

A locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. Here, we demonstrate that a 295T>C variant in the human ZRS, previously thought to represent a neutral polymorphism, acts as a dominant allele with reduced penetrance.

Clinical dividends from the molecular genetic diagnosis of craniosynostosis.

A dozen years have passed since the first genetic lesion was identified in a family with craniosynostosis, the premature fusion of the cranial sutures. Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for approximately 25% of craniosynostosis, whilst several additional genes make minor contributions. Using specific examples, we show how these discoveries have enabled refinement of information on diagnosis, recurrence risk, prognosis for mental development, and surgical planning.

Clinical dividends from the molecular genetic diagnosis of craniosynostosis.

A dozen years have passed since the first genetic lesion was identified in a family with craniosynostosis, the premature fusion of the cranial sutures. Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for approximately 25% of craniosynostosis, whilst several additional genes make minor contributions. Using specific examples, we show how these discoveries have enabled refinement of information on diagnosis, recurrence risk, prognosis for mental development, and surgical planning.

The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males.

Craniofrontonasal syndrome (CFNS) is an X-linked disorder that exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis, and additional minor malformations, but males are usually mildly affected with hypertelorism only. Despite this, males appear underrepresented in CFNS pedigrees, with carrier males encountered infrequently compared with affected females. To investigate these unusual genetic features of CFNS, we exploited the recent discovery of causative mutations in the EFNB1 gene, which encodes ephrin-B1, to survey the molecular alterations in 59 families (39 newly investigated and 20 published elsewhere).

Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype.

Heterozygous mutations of the homeobox genes ALX4 and MSX2 cause skull defects termed enlarged parietal foramina (PFM) and cranium bifidum (CB); a single MSX2 mutation has been documented in a unique craniosynostosis (CRS) family. However, the relative mutational contribution of these genes to PFM/CB and CRS is not known and information on genotype-phenotype correlations is incomplete. We analysed ALX4 and MSX2 in 11 new unrelated cases or families with PFM/CB, 181 cases of CRS, and a single family segregating a submicroscopic deletion of 11p11.

A further mutation of the FGFR2 tyrosine kinase domain in mild Crouzon syndrome.

We report a family heterozygous for a newly identified mutation in the tyrosine kinase I domain of the FGFR2 gene (1576A > G, encoding the missense substitution Lys526Glu), associated with variable expressivity of Crouzon syndrome, including clinical nonpenetrance. Our observations expand both the clinical and molecular spectrum of this unusual subset of FGFR2 mutations.

Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis.

Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3). This frequently occurs as a new mutation, manifesting one of the highest documented rates for any transversion in the human genome.