Search

Pathogenic variants in DDX3X have recently been identified to be a relatively common cause of intellectual disability in females. In this study, we describe six female probands, from five unrelated families, with five novel heterozygous variants in DDX3X, and the identification of potential germline mosaicism. Consistent features between this cohort and previously described cases include developmental delay or intellectual disability, growth disturbance and movement disorder. Common facial dysmorphism within the cohort include short palpebral fissures, micrognathia, bulbous nasal tip, protruding ears, high arched palate, thin upper vermillion and smooth philtrum. Novel clinical features identified from this cohort include facial dysmorphisms, perinatal complications, valgus feet deformity, lipoatrophy, dystonic episodes, and cutaneous mastocytosis. This case series attempts to expand the phenotype of the DDX3X syndrome; however, it remains heterogeneous. Description of further cases is required to more accurately identify the significance of novel phenotypes within this cohort.

New Zealand has a multiethnic population and a national cardiac inherited disease registry (Cardiac Inherited Disease Registry New Zealand [CIDRNZ]). Ancestry is reflected in the spectrum and prevalence of genetic variants in long QT syndrome (LQTS).The purpose of this study was to study the genetic testing yield and mutation spectrum of CIDRNZ LQTS probands stratified by self-identified ethnicity.A 15-year retrospective review of clinical CIDRNZ LQTS probands with a Schwartz score of ≥2 who had undergone genetic testing was performed.Of the 264 included LQTS probands, 160 (61%) reported as European, 79 (30%) NZ Māori and Pacific peoples (Polynesian), and 25 (9%) Other ethnicities, with comparable clinical characteristics across ethnic groups (cardiac events in 72%; age at presentation 28±19 years; corrected QT interval 512±55 ms). Despite comparable testing (5.3±1.4 LQTS genes), a class III-V LQTS variant was identified in 35% of Polynesian probands as compared with 63% of European and 72% of Other probands (P.0001). Among variant-positive CIDRNZ LQTS probands (n=148), Polynesians were more likely to have non-missense variants (57% vs 39% and 25% in probands of European and Other ethnicity, respectively; P=.005) as well as long QT syndrome type 1-3 variants not reported elsewhere (71% vs European 22% and Other 28%; P.0001). Variants found in multiple probands were more likely to be shared within the same ethnic group; P.01).Genetic testing of Polynesian LQTS probands has a lower diagnostic yield, despite comparable testing and clinical disease severity. Rare LQTS variants are more common in Polynesian LQTS probands. These data emphasize the importance of increasing the knowledge of genetic variation in the Polynesian population.

We report the results of a pilot project for clinical DNA sequencing in New Zealand. This project aimed to estimate the diagnostic yield of next generation sequencing in the New Zealand clinical en...

Background To review long QT syndrome molecular autopsy results in sudden unexplained death in young (SUDY) between 2006 and 2013 in New Zealand. Methods Audit of the LQTS molecular autopsy results, cardiac investigations and family screening data from gene-positive families. Results During the study period, 365 SUDY cases were referred for molecular autopsy. 128 cases (35%) underwent LQTS genetic testing. 31 likely pathogenic variants were identified in 27 cases (21%); SCN5A (14/31, 45%), KCNH2 (7/31, 22%), KCNQ1 (4/31, 13%), KCNE2 (3/31, 10%), KCNE1 (2/31, 7%), KCNJ2 (1/31, 3%). Thirteen variants (13/128, 10%) were ultimately classified as pathogenic. Most deaths (63%) occurred during sleep. Gene variant carriage was more likely with a positive medical history (mostly seizures, 63% vs 36%, p = 0.01), amongst females (36% vs 12%, p = 0.001) and whites more than Maori (31% vs 0, p = 0.0009). Children 1–12 years were more likely to be gene-positive (33% vs 14%, p = 0.02). Family screening identified 42 gene-positive relatives, 18 with definitive phenotypic expression of LQTS/Brugada. 76% of the variants were maternally inherited (p = 0.007). Further family investigations and research now support pathogenicity of the variant in 13/27 (48%) of gene-positive cases. Conclusion In New Zealand, variants in SCN5A and KCNH2, with maternal inheritance, predominate. A rare variant in LQTS genes is more likely in whites rather than Maori, females, children 1–12 years and those with a positive personal and family history of seizures, syncope or SUDY. Family screening supported the diagnosis in a third of the cases. The changing classification of variants creates a significant challenge.

Purpose : The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. Methods : A 20-gene panel was designed based on the genes’ association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. Results : Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre–Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. Conclusion : These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre–Chotzen syndrome.

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymkinsT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits., During embryogenesis, the cytoplasmic protein Myomarker (MYMK) mediates muscle fibre formation by fusion of myoblasts. Here, the authors identify autosomal recessive mutations in MYMK that cause Carey-Fineman-Ziter syndrome in humans, and model the disease variants in zebrafish.

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars(1,2). High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer

The relatively rare proximal microdeletion of 17q12 (including deletion of the HNF1B gene) is associated with the renal cysts and diabetes syndrome. Recent reports have suggested that there may also be an association between this microdeletion and learning difficulties/autism. This case report describes one of only a few reported families segregating the 17q12 microdeletion, but which highlights the nonpenetrance and variable expressivity of multiple features of this condition.

The absence of a definitive genetic test for the autosomal recessive condition Schinzel-Giedion syndrome is a significant handicap to the recognition of this disorder. Radiological features have been an important aspect of many of the published cases. In a series of six cases, we now establish a consistency among many of the radiological features in affected cases which will be an important diagnostic aid in identifying future cases. This is confirmed by reference to an extensive review of previously published instances of the syndrome. Moreover, the clinical data, including previously unpublished photographs, which we detail from our patients will assist in enhanced diagnosis in the future.

Objectives To assess the opinions of individuals with mucopolysaccharidoses (MPS) and their parents regarding the use of enzyme replacement therapy (ERT). Study design A validated questionnaire, including hypothetical clinical scenarios about ERT for MPS, was distributed to members of MPS support groups in the United States and Australia. Results The questionnaire was completed by 249 MPS support group members. Overall, 92% were in favor of ERT where MPS causes severe physical problems but does not affect intellect, and 69% were in favor of ERT where the physical limitations are mild and intellect is spared. Only 47% were in favor of ERT where severe physical and intellectual problems are well established; however, 77% were in favor of ERT in this situation if treatment begun early prolongs life and improves quality of life. Conclusion Most respondents were in favor of ERT for MPS, even where it would not alter the intellectual deterioration. The medical community has a responsibility to advocate for their patients in situations where ERT is appropriate and recognize the economic burden and "family function burden" ERT can incur.

Background— Large gene rearrangements, not detectable by standard molecular genetic sequencing techniques, are present in a minority of patients with long QT syndrome. We aimed to screen for large rearrangements in genes responsible for long QT syndrome as part of the molecular autopsy of a 36-year-old woman who died suddenly and had a negative autopsy. A retrospective analysis of an ECG identified a long QT interval, but sequencing of known LQT genes was uninformative. Methods and Results— Array comparative genomic hybridization was used to screen for deletions and duplications in 101 genes implicated in cardiac disorders and sudden death using a postmortem blood sample. A 542 kb deletion encompassing the entire KCNJ2 gene was identified in the decedent. The mother had electrocardiographic U-wave changes consistent with Andersen–Tawil syndrome and exaggerated by exercise but none of the characteristic noncardiac features. Fluorescence in situ hybridization confirmed the deletion in the decedent and established its presence in the mother. Conclusions— A novel application of array comparative genomic hybridization and fluorescence in situ hybridization has identified that long QT syndrome and sudden cardiac death may occur as a result of a deletion of an entire gene. The case also supports recent research suggesting that noncardiac features of Andersen–Tawil syndrome occur only with missense or minor gene rearrangements in the KCNJ2 gene, resulting in a dominant negative effect on Kir2.x channels.

Contains fulltext : 88081.pdf (Publisher’s version ) (Closed access) Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect. 01 juni 2010

Fryns-Aftimos syndrome (MIM 606155) is a rare condition characterised by pachygyria, severe mental retardation, epilepsy and characteristic facies. We report a patient who, unlike previously reported cases, remains seizure free with relatively mild developmental delay and facial phenotype.

We describe two patients who have hypochondroplasia with medial temporal lobe dysgenesis. This association has only been reported once before. Both patients had an FGFR3 mutation: 1620C --> A, resulting in Asn540Lys. FGFR3 is expressed in the brain during development and plays a role in hippocampal formation. We suggest FGFR3 mutations might cause cerebral malformations in hypochondroplasia as well as in thanatophoric dysplasia. Further neuroimaging studies of patients with hypochondroplasia and epilepsy or developmental delay may clarify the proportion of patients with hypochondroplasia who have this pattern of central nervous system abnormalities.

Background Long QT syndrome (LQTS) prevalence is estimated at 4 of 10,000 based on community electrocardiogram (ECG) screening, about which there is disagreement regarding efficacy, accuracy, cost-effectiveness, and practicality. Family studies of autosomal dominant conditions such as LQTS have revealed 8–9gene-positive family members per proband. Objective To evaluate a cardiac/genetic registry and family screening program as a tool to identify LQTS in the community. Methods Possible LQTS probands were referred to the New Zealand Cardiac Inherited Disease service. The registry was first established in the northern region (population 2.03 million), including central Auckland (population 0.46 million). After clinical evaluation, genetic testing and family cascade screening were initiated. Genotype-positive individuals were classified as definite LQTS, and others were classified as definite or probable LQTS by clinical and ECG criteria. Results One hundred twelve probands were identified (presentation: 7 sudden death, 82 cardiac event, 16 ECG abnormality, and 7 sudden death of a family member). Following cascade screening, 309 patients with LQTS were identified (248 definite and 61 probable). Two hundred twenty patients had LQTS-causing mutations identified (120 [55%] LQT1, 78 [35%] LQT2, 19 [9%] LQT3, 1 [0.5%] LQT 5, and 2 [1%] LQT7). Thus far, an average of 2.1 definitely or probably affected family members have been identified per proband. The community detection rate is 1.5 of 10,000 for the whole region and 2.2 of 10,000 in Auckland. Conclusions A high level of community detection of LQTS is possible using a clinical registry. With adequate resourcing, this has the potential to be an effective alternative to community ECG screening.

An amniotic fluid sample from anin vitrofertilized pregnancy was referred for cytogenetic analysis based on a Down syndrome screening risk of 1 : 21. Routine cytogenetic analysis showed a nonmosaic karyotype of 46,XX,r(21)(p11.2q22.3), with partial monosomy for chromosome 21 due to a ring chromosome replacing one of the normal homologues. Detailed ultrasound scanning for the remainder of the pregnancy did not reveal any unusual findings. Parental bloods showed that the mother was mosaic for the ring 21 with a karyotype of 46,XX,r(21)(p11.2q22.3)/46,XX and the father had an unrelated Robertsonian translocation, with a karyotype of 45,XY,rob(13;14)(q10;q10). Microarray analysis of cultured amniocytes determined the extent of the deletion of chromosome 21 material in the ring. The parents were given genetic counselling, and a phenotypically normal female baby was delivered at term. This case highlights the importance of karyotyping as an initial step in the management of couples referred forin vitrofertilization.

Background Retrospective investigation of sudden unexplained death in the young (SUDY) reveals that a high proportion is due to inherited heart disease. Objective The purpose of this study was to ascertain the diagnostic value of postmortem long QT (LQT) genetic analysis in a prospective study of SUDY victims 1–40 years old. Methods Denaturing high-performance liquid chromatography or direct sequencing of LQT genes 1, 2, 3, 5, and 6 was performed, in a National New Zealand protocol, in SUDY victims aged 1–40 years. Results Over 26 months (2006–2008), DNA was stored at autopsy from 52 victims of sudden unexpected death. Further testing revealed a diagnosis in 19 cases (poisoning 4, dilated cardiomyopathy 3, myocarditis 3, other 9). The remaining 33 cases underwent genetic testing (age at death 18 months–40 years, median 25 years). Eighteen (55%) died during sleep or at rest, and 7 (21%) died during light activity. Rare missense variants in LQT genes were found in 5 (15%) cases (confidence interval 3%–27%): T96R in KCNQ1 (11-year-old male), P968L in KCNH2 (32-year-old female), P2006A in SCN5A (34-year-old female), and R67H and R98W in KCNE1 (17- and 38-year-old females, respectively). Evidence of pathogenicity was provided by in vitro evidence (T96R), family phenotype–genotype co-segregation (R98W, P2006A), and/or previous reports (R67H, P968L, P2006A, R98W). Family cardiac investigation was possible in 23 (70%) families and revealed probable cause of death for 5 (15%) other victims (confidence interval 3%–27%). Conclusion Most community SUDY occurs at rest or during light activity. A diagnostic rate of 15% supports the transition of LQT genetic autopsy, combined with family investigation, into routine medical practice.

Background: There has been an exponential increase in the number of genes implicated in inherited retinal disease over the last decade, but the genetic and phenotypic heterogeneity limited mutation detection. The high cost of sequencing and long turn around times meant that gene testing was not a viable option, particularly in New Zealand. Recently, advancements including development of micro-array-based mutation analysis and non-for-profit laboratories have resulted in affordable and time-efficient testing. This has enabled genetic diagnostics to become an integral component of the work-up for inherited retinal disease. Methods: Genetic testing for inherited retinal disorders was initiated via the Ocular Genetic Clinic in Auckland 2 years ago. A retrospective audit of genetic testing over this period was carried out. The results of these tests and outcomes are discussed. Results: Thirty-five probands have undergone genetic testing for retinal disorders. This has included X-Linked Retinoschisis, Leber Congenital Amaurosis, Retinitis Pigmentosa, Albinism, Achromatopsia, Usher syndrome, Stargardt disease and Mitochondrial disease. Of these, 54% of tests (19/35) showed a rare variant or pathogenic mutation. Three couples have proceeded to investigate the options of prenatal diagnosis and/or pre-implantation genetic diagnosis. Conclusion: The introduction of genetic testing, largely via disease arrays, has been highly successful at clarifying disease genotype in our cohort. It is now a timely and cost-effective investigation that should be elemental to the assessment of inherited retinal disease. Genetic testing in an opportune fashion permits genetic counselling, enables families to make reproductive choices and might allow the possibility of gene therapy interventions.

We have conducted a study to assess the opinions of parents of individuals with mucopolysaccharidoses (MPS) and adults with MPS regarding newborn screening (NBS) for this condition, as testing is now technically possible. A questionnaire including a number of hypothetical clinical scenarios about NBS for MPS was distributed to members of MPS support groups from United States and Australia. Questionnaires were returned by 249 members of the US (40% response) and Australian (38% response) support groups. Eleven respondents were adults with MPS and the rest were parents of individuals with MPS. Eighty-six percent of respondents indicated that they would have wanted NBS for their own children. Ninety-seven percent supported the use of NBS for MPS in situations where early treatment that favorably impacts on disease outcome is available, 87% supported NBS when a severe form of MPS was diagnosed, but no treatment is available that improves the long-term outcome and 84% supported NBS for mild MPS where no disease-modifying treatment is available. The most common reason cited in support of NBS was that NBS could avoid a delay in diagnosis and the accompanying distress that delayed diagnosis created. This study has identified strong support for the introduction of NBS for MPS from this group. Psychosocial benefits of screening may outweigh potential harms.

Multi-gene testing panels provided by clinical laboratories have become increasingly available and affordable and have been used since 2008 in South Australia. We audited consecutive patients diagnosed with cardiomyopathy or channelopathy and referred to the SA Clinical Genetics Service for genetic testing between 1 January 2008 and 31 December 2013. 66 probands with cardiac channelopathy were identified, 58 with Long QT syndrome (LQTS), 5 with Brugada syndrome, and 3with other disorders. 62 of these probandswere tested. The 60 completed tests identified 28% with pathogenic variants (All LQTS 29%, familial LQTS 43%, sporadic LQTS 20%) and 13% with variants of uncertain significance (VUS). Proband testing in channelopathy enabled cascade testing in 41 patients, 10 for confirmatory and 31 for predictive testing. 94 probandswith cardiomyopathywere identified, 73 with hypertrophic cardiomyopathy (HCM), 10 with dilated cardiomyopathy, 4 with arrhythmogenic ventricular dysplasia, and 7 with other cardiomyopathies. 77 of these probands were tested. The 70 completed tests identified 47% with pathogenic variants (All HCM 46%, familial HCM 74%, sporadic HCM 22%) and 14% with a VUS. Proband testing in cardiomyopathy enabled cascade testing in 24 patients, 3 for confirmatory and 21 for predictive testing. We found that the yield of genetic testing for cardiomyopathies was similar to published rates, but our yield of genetic testing for cardiac channelopathies was lower than published rates. VUS were found in a considerable proportion of patients. In vivo functional data exist for few variants.

We describe a newborn girl with incontinentia pigmenti (IP, MIM308300), unilateral acheiria, and fatal primary pulmonary hypertension. Limb deficiency has not been described previously in IP and pulmonary hypertension only on two previous occasions. A review of the cause of IP shows that these rare manifestations may not be unexpected, given the many roles of the underlying gene product.

A re-examination has been carried out of the region on chromosome 9 containing the locus responsible for Ferguson-Smith disease, or multiple self-healing squamous epithelioma (MSSE/FSD); this is a rare autosomal dominant inherited condition first identified in the west of Scotland, that presents with multiple squamous cell skin carcinomas which grow, invade locally and then spontaneously regress. Approach: A 4Mb locus on chromosome 9 was earlier identified by genetic mapping in a cluster of families. In this study a wider region encompassing 24Mb around this earlier identified locus was examined using high-throughput sequencing with exon capture, followed by Sanger sequencing. Result: This effort identified mutations in the TGFBR1 gene in 18 out of 22 families diagnosed as affected by MSSE/FSD. These include 11 different mutations. The tumours occur in sun-exposed areas of the skin, and loss-of-heterozygosity in tumours is frequently seen. The sequence variants disturb the function of the TGFβRI receptor such that although heterozygous carriers are asymptomatic during development, loss of the second (wild-type) allele ablates the receptor function and leads to local cancer susceptibility. Conclusions: The nature of the mutations sets the mechanism apart from that involved in Marfan syndrome-related disorders, in which developmental defects in vasculature are also caused by mutations in this gene. The involvement of TGFβ receptors in this condition is intriguing as TGFβ pathway effects are known to be biphasic and opposing at different stages of cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-245. doi:10.1158/1538-7445.AM2011-LB-245