Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.
AIM Determining inclusion/exclusion criteria for cerebral palsy (CP) surveillance is challenging. The aims of this paper were to (1) define inclusion/exclusion criteria that have been adopted uniformly by surveillance programmes and identify where consensus is still elusive, and (2) provide an updated list of the consensus concerning CP inclusion/exclusion when a syndrome/disorder is diagnosed.METHOD Data were drawn from an international survey of CP registers, the New South Wales CP Register (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003), the Western Australian CP Register (1975Register ( -2008, and the Surveillance of CP in Europe (SCPE; 1976-1998). An expert panel used a consensus building technique, which utilized the SCPE 'decision tree' and the original 'What constitutes cerebral palsy?' paper as frameworks.RESULTS CP surveillance programmes agree on key clinical criteria pertaining to the type, severity, and origin of motor disorder in CP. Further work is warranted to reach agreement for (1) minimum age of survival and maximum age of postneonatal brain injury, and (2) metabolic disorders with highly variable clinical courses/responses to treatment. One hundred and ninety-seven syndromes/disorders were reviewed and advice on their inclusion/ exclusion is provided. INTERPRETATIONWhat constitutes CP will continue to evolve as diagnostics improve.Surveillance programmes throughout the world are committed to addressing their differences regarding inclusion/exclusion criteria for the umbrella term CP.Advances and changes in diagnostic modalities and medical technology since our 1998 publication 'What constitutes cerebral palsy?' 1 have led to requests to revise the paper. Since 1998 we have seen an increase in the number of CP surveillance programmes internationally and their desire for collaboration led to the first World CP Register Day in 2009.2 Inclusion/exclusion criteria in CP surveillance were key points discussed. It was acknowledged by participants that whilst each group must meet the specific needs of their own individual surveillance programme, it is advantageous to have consensus across programmes regarding core inclusion/exclusion criteria. Consensus in criteria provides opportunities to pool data across registers, increase power for research, monitor trends over time between and across regions, and to evaluate new population level interventions such as magnesium sulphate 3 and cooling. 4 Similarly, homogeneity of inclusion/exclusion criteria is advantageous for researchers using registers as a sampling frame for multicentre trials. This article seeks to (1) define inclusion/exclusion criteria that have been adopted uniformly by surveillance programmes and to illuminate areas where consensus about criteria could not be reached between surveillance programmes, and (2) provide an updated list of the consensus concerning the inclusion or exclusion of CP when a syndrome or disorder is diagnosed. the original 1998 paper 1 or identified in potential registrants of the New South Wales ...
Cerebral palsy (CP) is a term of convenience applied to a group of motor disorders of central origin defined by clinical description. It is not a diagnosis in that its application infers nothing about pathology, aetiology, or prognosis. It is an umbrella term covering a wide range of cerebral disorders which result in childhood motor impairment. The precise inclusion criteria vary with the objectives for using the term. For meaningful comparison of rates of CP, as performed by and between CP registers, it is important that the rates should be generated using the same criteria. As generally understood there must be motor impairment, and this impairment must stem from a malfunction of the brain (rather than spinal cord or muscles). Furthermore, the brain malfunction must be non‐progressive and it must be manifest early in life. For the purposes of comparisons of rates across time even when the condition meets all the above criteria, it must not historically have been excluded from the category of CP. This paper addresses the problem of standardizing the inclusion criteria for selecting people included on CP registers with particular reference to this last criterion.
BackgroundFetal akinesia/hypokinesia, arthrogryposis and severe congenital myopathies are heterogeneous conditions usually presenting before or at birth. Although numerous causative genes have been identified for each of these disease groups, in many cases a specific genetic diagnosis remains elusive. Due to the emergence of next generation sequencing, virtually the entire coding region of an individual’s DNA can now be analysed through “whole” exome sequencing, enabling almost all known and novel disease genes to be investigated for disorders such as these.MethodsGenomic DNA samples from 45 patients with fetal akinesia/hypokinesia, arthrogryposis or severe congenital myopathies from 38 unrelated families were subjected to next generation sequencing. Clinical features and diagnoses for each patient were supplied by referring clinicians. Genomic DNA was used for either whole exome sequencing or a custom-designed neuromuscular sub-exomic supercapture array containing 277 genes responsible for various neuromuscular diseases. Candidate disease-causing variants were investigated and confirmed using Sanger sequencing. Some of the cases within this cohort study have been published previously as separate studies.ResultsA conclusive genetic diagnosis was achieved for 18 of the 38 families. Within this cohort, mutations were found in eight previously known neuromuscular disease genes (CHRND, CHNRG, ECEL1, GBE1, MTM1, MYH3, NEB and RYR1) and four novel neuromuscular disease genes were identified and have been published as separate reports (GPR126, KLHL40, KLHL41 and SPEG). In addition, novel mutations were identified in CHRND, KLHL40, NEB and RYR1. Autosomal dominant, autosomal recessive, X-linked, and de novo modes of inheritance were observed.ConclusionsBy using next generation sequencing on a cohort of 38 unrelated families with fetal akinesia/hypokinesia, arthrogryposis, or severe congenital myopathy we therefore obtained a genetic diagnosis for 47 % of families. This study highlights the power and capacity of next generation sequencing (i) to determine the aetiology of genetically heterogeneous neuromuscular diseases, (ii) to identify novel disease genes in small pedigrees or isolated cases and (iii) to refine the interplay between genetic diagnosis and clinical evaluation and management.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0364-0) contains supplementary material, which is available to authorized users.
Hemifacial microsomia (HFM) is a common birth defect involving first and second branchial arch derivatives. The phenotype is extremely variable. In addition to craniofacial anomalies there may be cardiac, vertebral and central nervous system defects. The majority of cases are sporadic, but there is substantial evidence for genetic involvement in this condition, including rare familial cases that exhibit autosomal dominant inheritance. As an approach towards identifying molecular pathways involved in ear and facial development, we have ascertained both familial and sporadic cases of HFM. A genome wide search for linkage in two families with features of HFM was performed to identify the disease loci. In one family data were highly suggestive of linkage to a region of approximately 10.7 cM on chromosome 14q32, with a maximum multipoint lod score of 3.00 between microsatellite markers D14S987 and D14S65. This locus harbours the Goosecoid gene, an excellent candidate for HFM based on mouse expression and phenotype data. Coding region mutations were sought in the familial cases and in 120 sporadic cases, and gross rearrangements of the gene were excluded by Southern blotting. Evidence for genetic heterogeneity is provided by the second family, in which linkage was excluded from this region.
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