ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder.

ACTB encodes ß-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, ß-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic ß-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, ß-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.

Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.

Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs(∗)6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome.

Novel mutations in BCOR in three patients with oculo-facio-cardio-dental syndrome, but none in Lenz microphthalmia syndrome.

Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant condition with male lethality characterized by microphthalmia, congenital cataracts, facial dysmorphic features, congenital heart defects, and dental anomalies. Mutations in BCOR (BCL6 co-repressor) located in Xp11.4 have been described to cause OFCD syndrome. Lenz microphthalmia syndrome is inherited in an X-linked recessive pattern comprising microphthalmia/anophthalmia, mental retardation, malformed ears, digital, skeletal, and urogenital anomalies (synonym: microphthalmia with associated anomalies (MAA)). One locus for MAA has been mapped to Xq27-q28. Nonetheless, linkage and subsequent mutation analysis revealed a single missense mutation (p.P85L) in BCOR in a large family with presumed Lenz microphthalmia syndrome (MAA2). We describe novel mutations in BCOR in three patients with OFCD syndrome, two small deletions (c.2488_2489delAG and c.3286delG) and a submicroscopic deletion of about 60 kb encompassing at least BCOR exons 2-15. No BCOR mutation was detected in eight patients with Lenz microphthalmia syndrome. Our data confirm that BCOR is the causative gene for OFCD syndrome; however, the failure to identify any mutation in patients with Lenz microphthalmia syndrome together with the oligosymptomatic phenotype in the reported MAA2 patients suggest that BCOR is not the major gene for this syndrome.

Segmentally arranged basaloid follicular hamartomas with osseous, dental and cerebral anomalies: a distinct syndrome.

A 39-year-old man presented with multiple basaloid follicular hamartomas involving the right side of his body in a systematized pattern following Blaschko's lines. His right leg was 22.5 cm shorter than the left, and rudimentary pre-axial polydactyly was noted on the left hand and the right foot. The teeth of the right maxilla were hypoplastic. DNA analysis of blood lymphocytes and fibroblasts from lesional skin did not reveal any mutation in the Patched gene. On account of this case and of 8 similar cases found in th e literature, the spectrum of a distinct syndrome is delineated. Ipsilateral extracutaneous defects include cervical ribs, polydactyly, malformed thumb and disproportionate overgrowth or deficient growth of limb bones; dental anomalies in the form of anodontia, hypodontia or ameloblastoma; and cerebral defects such as mental retardation, unsteady gait, meningioma and optic glioma. The cutaneous lesions of this syndrome should not be called "basal cell naevus" as this will lead to continuing confusion with Gorlin syndrome. The molecular basis of the disorder remains to be elucidated.

Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis.

The Shprintzen-Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective-tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down-slanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed.