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We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family 1 of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling 2 . The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway 3 , 4 . To our knowledge, this is the first report of mutations in the SPRY ( SPROUTY )/ SPRED family of genes in human disease.

Vanneste and her colleagues describe an array-based approach for scoring genome-wide DNA copy number variations and loss of heterozygosity in single cells. They show that chromosome instability patterns, reminiscent of those seen in human cancers, are also common in cleavage-stage in vitro –fertilized embryos. Such findings during early human embryogenesis could provide a basis for the low fecundity and high miscarriage rate in humans pages 490–491 .. Chromosome instability is a hallmark of tumorigenesis. This study establishes that chromosome instability is also common during early human embryogenesis. A new array-based method allowed screening of genome-wide copy number and loss of heterozygosity in single cells. This revealed not only mosaicism for whole-chromosome aneuploidies and uniparental disomies in most cleavage-stage embryos but also frequent segmental deletions, duplications and amplifications that were reciprocal in sister blastomeres, implying the occurrence of breakage-fusion-bridge cycles. This explains the low human fecundity and identifies post-zygotic chromosome instability as a leading cause of constitutional chromosomal disorders.

William Dobyns, Daniela Pilz and colleagues show that de novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome, a developmental disorder characterized by distinct craniofacial features, ocular colobomata and defects in neuronal migration. Brain malformations are individually rare but collectively common causes of developmental disabilities 1 , 2 , 3 . Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations 4 , 5 . Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect 6 , 7 . Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin–encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations ( ACTB , encoding p.Arg196His, and ACTG1 , encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.

A tiling X-chromosome-specific genomic array with a theoretical resolution of 80 kb was developed to screen patients with idiopathic mental retardation (MR) for submicroscopic copy number differences. Four patients with aberrations previously detected at lower resolution were first analyzed. This facilitated delineation of the location and extent of the aberration at high resolution and subsequently, more precise genotype-phenotype analyses. A cohort of 108 patients was screened, 57 of which were suspected of X-linked mental retardation (XLMR), 26 were probands of brother pairs, and 25 were sporadic cases. A total of 15 copy number changes in 14 patients (13%) were detected, which included two deletions and 13 duplications ranging from 0.1 to 2.7 Mb. The aberrations are associated with the phenotype in five patients (4.6%), based on the following criteria: de novo aberration; involvement of a known or candidate X-linked nonsyndromic(syndromic) MR (MRX(S)) gene; segregation with the disease in the family; absence in control individuals; and skewed X-inactivation in carrier females. These include deletions that contain the MRX(S) genes CDKL5, OPHN1, and CASK, and duplications harboring CDKL5, NXF5, MECP2, and GDI1. In addition, seven imbalances were apparent novel polymorphic regions because they do not fulfill the proposed criteria. Taken together, our data strongly suggest that not only deletions but also duplications on the X chromosome contribute to the phenotype more often than expected, supporting the increased gene dosage mechanism for deregulation of normal cognitive development. Hum Mutat 28(10), 1034-1042, 2007. © 2007 Wiley-Liss, Inc.

We have recently reported a missense mutation in exon 4 of the tubulin alpha 1A (Tuba1a) gene in a hyperactive N-ethyl-N-nitrosourea (ENU) induced mouse mutant with abnormal lamination of the hippocampus. Neuroanatomical similarities between the Tuba1a mutant mouse and mice deficient for Doublecortin (Dcx) and Lis1 genes, and the well-established functional interaction between DCX and microtubules (MTs), led us to hypothesize that mutations in TUBA1A (TUBA3, previous symbol), the human homolog of Tuba1a, might give rise to cortical malformations. This hypothesis was subsequently confirmed by the identification of TUBA1A mutations in two patients with lissencephaly and pachygyria, respectively. Here we report additional TUBA1A mutations identified in six unrelated patients with a large spectrum of brain dysgeneses. The de novo occurrence was shown for all mutations, including one recurrent mutation (c.790C>T, p.R264C) detected in two patients, and two mutations that affect the same amino acid (c.1205G>A, p.R402H; c.1204C>T, p.R402C) detected in two other patients. Retrospective examination of MR images suggests that patients with TUBA1A mutations share not only cortical dysgenesis, but also cerebellar, hippocampal, corpus callosum, and brainstem abnormalities. Interestingly, the specific high level of Tuba1a expression throughout the period of central nervous system (CNS) development, shown by in situ hybridization using mouse embryos, is in accordance with the brain-restricted developmental phenotype caused by TUBA1A mutations. All together, these results, in combination with previously reported data, strengthen the relevance of the known interaction between MTs and DCX, and highlight the importance of the MTs/DCX complex in the neuronal migration process. Hum Mutat 28(11), 1055-1064, 2007. © 2007 Wiley-Liss, Inc.

The Wiskott-Aldrich syndrome protein (WASP; encoded by the gene WAS ) and its homologs are important regulators of the actin cytoskeleton, mediating communication between Rho-family GTPases and the actin nucleation/crosslinking factor, the Arp2/3 complex 1 . Many WAS mutations impair cytoskeletal control in hematopoietic tissues, resulting in functional and developmental defects that define the X-linked Wiskott-Aldrich syndrome (WAS) and the related X-linked thrombocytopenia 2 (XLT). These diseases seem to result from reduced WASP signaling, often through decreased transcription or translation of the gene 3 , 4 , 5 , 6 , 7 , 8 . Here we describe a new disease, X-linked severe congenital neutropenia (XLN), caused by a novel L270P mutation in the region of WAS encoding the conserved GTPase binding domain (GBD). In vitro , the mutant protein is constitutively activated through disruption of an autoinhibitory domain in the wild-type protein, indicating that loss of WASP autoinhibition is a key event in XLN. Our findings highlight the importance of precise regulation of WASP in hematopoietic development and function, as impairment versus enhancement of its activity give rise to distinct spectra of cellular defects and clinical phenotypes.

BackgroundGermline mutations in the CHRNG gene that encodes the γ subunit of the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) or the lethal form (LMPS) of multiple pterygium syndrome (MPS). In addition CHRNG mutations and mutations in other components of the embryonal acetylcholine receptor may present with fetal akinesia deformation sequence (FADS) without pterygia.MethodsIn order to elucidate further the role of CHRNG mutations in MPS/FADS, this study evaluated the results of CHRNG mutation analysis in 100 families with a clinical diagnosis of MPS/FADS.ResultsCHRNG mutations were identified in 11/41 (27%) of families with EVMPS and 5/59 (8%) with LMPS/FADS. Most patients with a detectable CHRNG mutation (21 of 24 (87.5%)) had pterygia but no CHRNG mutations were detected in the presence of central nervous system anomalies.DiscussionThe mutation spectrum was similar in EVMPS and LMPS/FADS kindreds and EVMPS and LMPS phenotypes were observed in different families with the same CHRNG mutation. Despite this intrafamilial variability, it is estimated that there is a 95% chance that a subsequent sibling will have the same MPS phenotype (EVMPS or LMPS) as the proband (though concordance is less for more distant relatives). Based on these findings, a molecular genetic diagnostic pathway for the investigation of MPS/FADS is proposed.

BackgroundManitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described.Methods and resultsThis study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1bat/bat mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome.ConclusionsThe milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS–FREM complex diseases.

X‐linked mental retardation (XLMR) is a heterogeneous disorder that affects approximately 2 in 1000 males. JARID1C/SMCX is relatively new among the known XLMR genes, and seven different mutations have been identified previously in this gene [Jensen LR et al., Am. J. Hum. Genet. 76:227–236, 2005]. Here, we report five novel JARID1C mutations in five XLMR families. The changes comprise one nonsense mutation (p.Arg332X) and four missense mutations (p.Asp87Gly; p.Phe642Leu; p.Arg750Trp; p.Tyr751Cys) affecting evolutionarily conserved amino acids. The degree of mental retardation in the affected males ranged from mild to severe, and some patients suffered from additional disorders such as epilepsy, short stature, or behavioral problems. This study brings the total number of reported JARID1C mutations to twelve. In contrast to other XLMR genes in which mutations were found only in single or very few families, JARID1C appears to be one of the more frequently mutated genes in this disorder. © 2006 Wiley‐Liss, Inc.

Germline mutations of the APC gene are responsible for familial adenomatous polyposis (FAP). Most of the mutations are protein truncating mutations and are spread over the coding region. Rare whole‐gene deletions or exonic deletions have been described. From a series of 85 patients clinically diagnosed with FAP or attenuated FAP (AAPC) in our center, 30 (35%) were found to have truncating or missense mutations. We have now screened the remaining 55 patients for exonic deletions or duplications, first by semi‐quantitative PCR and later by multiplex ligation‐dependent probe amplification (MLPA). Three whole‐gene deletions and one exon 14 deletion were found (5% of patients). The whole‐gene deletions were confirmed by fluorescence in situ hybridization (FISH) analysis, and the breakpoints of the exon 14 deletion could be determined using long range PCR. Further characterization of the whole gene deletions was performed using extragenic polymorphic markers and/or semi‐quantitative PCR. We could demonstrate that the deletions do not encompass the MCC gene. Interestingly, the phenotype of the deletion patients was not different from that of patients with truncating mutations. The polyp numbers ranged from attenuated to profuse polyposis and the interfamilial variability of disease phenotype was as in other FAP families. In none of the 28 AAPC patients included in this study, was a large deletion found, while 15% of the patients with classical polyposis had a genomic deletion. It corroborates recently published data, suggesting that large deletions may occur with a frequency higher than 10% in mutation‐negative patients with a classical polyposis. In this article, we have included an overview of genomic rearrangements in the 5q21 region. Hum Mutat 25:125–134, 2005. © 2005 Wiley‐Liss, Inc.