Bardet-Biedl syndrome (BBS; MIM 209900) is a recessive heterogeneous ciliopathy characterized by retinitis pigmentosa (RP), postaxial polydactyly, obesity, hypogonadism, cognitive impairment and ...kidney dysfunction. So far, 20 BBS genes have been identified, with the last reported ones being found in one or very few families. Whole-exome sequencing was performed in a consanguineous family in which two affected children presented typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism and cognitive impairment) without any mutation identified in known BBS genes at the time of the study. We identified a homozygous splice-site mutation (NM_015662.2: c.4428+3A>G) in both affected siblings in the last reported BBS gene, namely, Intraflagellar Transport 172 Homolog (IFT172). Familial mutation segregation was consistent with autosomal recessive inheritance. IFT172 mutations were initially reported in Jeune and Mainzer-Saldino syndromes. Recently, mutations have also been found in isolated RP and Bardet-Biedl-like ciliopathy. This is the second report of IFT172 mutations in BBS patients validating IFT172 as the twentieth BBS gene (BBS20). Moreover, another IFT gene, IFT27, was already associated with BBS, confirming the implication of IFT genes in the pathogenesis of BBS.
Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD ...in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified. However, despite high-throughput sequencing studies, the cause of the disease remains unknown in most patients, and several studies support more complex inheritance and the role of environmental factors and/or epigenetics in the pathophysiology of CAKUT. Here, we report the targeted exome sequencing of 330 genes, including genes known to be involved in CAKUT and candidate genes, in a cohort of 204 unrelated patients with CAKUT; 45% of the patients were severe fetal cases. We identified pathogenic mutations in 36 of 204 (17.6%) patients. These mutations included five
heterozygous loss of function mutations/deletions in the PBX homeobox 1 gene (
), a gene known to have a crucial role in kidney development. In contrast, the frequency of
and
variants recently reported as pathogenic in CAKUT did not indicate causality. These findings suggest that
is involved in monogenic CAKUT in humans and call into question the role of some gene variants recently reported as pathogenic in CAKUT. Targeted exome sequencing also proved to be an efficient and cost-effective strategy to identify pathogenic mutations and deletions in known CAKUT genes.
Proteases, lipases and carbohydrases are digestive enzyme sub-classes that influence the digestive capacity of abalone. In a 12-week study, the effects of age, water temperature and dietary protein ...levels on digestive enzyme activity in greenlip abalone (Haliotis laevigata) were investigated. One- and 2-year old abalone were fed diets with crude protein (CP) levels from 24 to 36% (18.0–28.6% digestible protein) and cultured at 14, 18 and 22°C. Diets were formulated to be isoenergetic (12.5MJkg−1 digestible energy) and isolipidic (3.6% crude lipid). Trypsin, α-amylase and lipase activities were measured, and were influenced differently by abalone age, water temperature and dietary protein levels. Lipase and α-amylase activities significantly increased as water temperatures were raised. In contrast, trypsin activity was not affected by water temperature. Trypsin activity of 2-year old abalone was significantly lower (53%) than that of 1-year old abalone. The α-amylase activities of 1-year old abalone were significantly up-regulated as dietary protein levels increased. In contrast, 2-year old abalone down-regulated α-amylase activity by 55% when fed 33% CP, compared to abalone fed 30% CP. The significant trypsin activity down-regulation in 2-year old abalone compared to 1-year old animals provides further support to reducing dietary protein for 2-year old abalone to optimise cultured greenlip abalone production. Significantly higher α-amylase activity in 1-year old abalone as starch levels were reduced indicates a compensatory effect in abalone fed carbohydrate deficient diets. Further research is recommended to optimise the protein to energy ratio for different age classes of greenlip abalone, especially when fed high dietary protein levels.
Statement of relevance: Results may contribute to further diet development research
•Abalone enzyme activities were influenced differently by age, temperature and protein levels.•Trypsin activities of 2-year old abalone were significantly lower (53%) than 1-year old abalone.•Results may contribute to further diet development research for greenlip abalone.
Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by ...café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual-a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with 'classical', clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype-phenotype association is fundamental to accurate prognostication for families and caregivers.
Wiedemann-Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic ...variants in the
gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare
variants can be challenging. A genome-wide DNA methylation episignature for
-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the
gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from
mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
Summer mortality (SM), a disease caused by an interaction between biotic and abiotic environmental factors at high water temperatures (>22°C), impacts health, growth and mortality (up to 50%) of ...larger (≥60mm) cultured abalone in southern Australia. We aimed to determine if dietary intervention could alleviate mortality demonstrated by abalone at high water temperatures. As this issue is most relevant to farm production, we aimed to demonstrate that different mortality patterns are evident for 2- and 3-year-old greenlip abalone (Haliotis laevigata Donovan), irrespective of reproductive state, and to provide potential, practical solutions to this issue. Growth rate, feed intake and haemolymph variables were measured. To test if dietary intervention could minimise mortality at high water temperatures, we selected a commercial diet routinely fed on-farm when SM occurred, as a negative survival control, and live macroalgae (Ulva lactuca Linnaeus) as a positive survival control. In Experiment 1, 30mm 2-year-old and 70mm 3-year-old abalone were subjected to water temperatures of 18, 22 and 26°C for 36days. In Experiment 2, 60mm 3-year-olds were subjected to 22 and 26°C for 38days. In Experiment 1, survival was >95% for all treatments at 18 and 22°C (P>0.05); whereas, survival was significantly reduced by 35% in 3-year-olds fed the commercial diet at 26°C compared to all other treatments (P<0.05). In Experiment 2, there was no mortality at 22°C. At 26°C, survival was significantly reduced by 50% (P<0.05) for the commercial diet, whereas, survival was >97% for the U. lactuca diet. We demonstrated that dietary intervention reduced mortality in larger abalone at 26°C. We also demonstrated a pattern of mortality in response to high water temperatures that differed for age classes. This information is invaluable for further systematic research to alleviate on-farm abalone mortality associated with high summer water temperatures, particularly in the areas of nutritional or therapeutic intervention.
•Dietary intervention may alleviate mortality of abalone at high water temperatures•Survival patterns in this study similar to what occurs on farm
Bardet-Biedl syndrome (BBS; MIM 209900) is a rare ciliopathy characterized by retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. ...Mutations in 22 BBS genes have been identified to cause the disease. We report a family with typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, cognitive impairment, and atrioventricular septal defect) mutated in
. IFT27 is part of the Intraflagellar transport (IFT), a bidirectional mechanism allowing the protein motility within the cilia. Using whole exome sequencing, two compound heterozygous mutations were found in the proband (NM_006860.4:c.104A > G;349+1G > T, p.Tyr35Cys;?) consistent with the expected autosomal recessive inheritance mode. These two mutations have already been reported but independently in other families and lacking either familial segregation or functional validation. This is the third report of
mutations in BBS patients confirming
as a BBS gene (
). Mutations in IFT genes (
and
) confirm the IFT-pathway as a pathomechanism for BBS.
Heterozygous activating variants in platelet‐derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile ...myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long‐term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS‐like disorders and suggest vascular imaging is indicated in these patients.
High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual ...disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt-Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.
Land-based grow-out of greenlip abalone (Haliotis laevigata) in Australia is predominantly practiced using a single-diet feeding strategy, despite geographical and seasonal differences in water ...temperature that influence feed intake and growth. This 12-wk study investigated the interactions between 2 abalone year classes (1 y old, 1.8 g; 2 y old, 22.9 g), 3 water temperatures (14°C, 18°C, and 22°C), and 4 dietary protein levels (1 y old: 27%, 30%, 33%, and 36% crude protein; 2 y old: 24%, 27%, 30%, and 33% crude protein) to evaluate the potential to use diets to suit specific water temperatures and aged animals. Diets were formulated to be isoenergetic (∼12.5 MJ/kg digestible energy), and contain fat levels of ∼3.6% and digestible protein levels ranging from 17.99%–28.57%. Feed was fed to excess daily and uneaten food was collected. Temperature significantly affected the specific growth rate of both year classes of abalone. There was no significant effect of dietary protein level on specific growth rate; however, abalone compensated for a reduction of dietary protein by consuming more feed. This observation was evident with significant increases in feed conversion ratios as dietary protein levels decreased for both year classes. With the exception of abalone grown at 14°C, when protein deposition decreased with increasing dietary protein level, protein deposition increased with an increase in dietary protein for both year classes. For 1-y-old abalone, as temperature increased from 14-22°C, the optimum crude dietary protein levels increased from -29%-∼35%. For 2-y-old abalone, the optimum crude protein level appeared to be less, and increased from 24% at 14°C to 34% at 22°C. There is scope to use multidiet feeding strategies in the production of greenlip abalone.
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