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1.
Neuropediatrics ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779033

RESUMO

BACKGROUND: A homozygous founder mutation in MTPAP/TENT6, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered. OBJECTIVE: To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families. METHODS: Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts. RESULTS: Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls. CONCLUSION: Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.

2.
Am J Med Genet A ; 179(10): 2152-2157, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321886

RESUMO

Mowat-Wilson syndrome (MWS) is a complex genetic disorder associated with heterozygous variation in ZEB2. It is mainly characterized by moderate-to-severe intellectual disability, facial dysmorphism, epilepsy, and various malformations including Hirschsprung disease, corpus callosum anomalies, and congenital heart defects. It is rarely diagnosed prenatally and there is limited information available on the prenatal phenotype associated with MWS. Here we report the detection of a heterozygous de novo nonsense variant in ZEB2 by whole exome sequencing in a fetus with microphthalmia in addition to cardiac defects and typical MWS facial dysmorphism. As the prenatal phenotypic spectrum of MWS expands, the routine addition of fetal genomic testing particularly in the presence of multiple malformations will increase both the sensitivity and specificity of prenatal diagnostics.

3.
Am J Med Genet A ; 179(8): 1585-1590, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31175705

RESUMO

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain-of-function mutations in the regulatory (SUR2) and pore-forming (Kir6.1) subunits of KATP channels, respectively, suggesting that channel-blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg-1 kg-1 day-1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg-1 kg-1 day-1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS.

4.
Hum Mutat ; 40(10): 1813-1825, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31215115

RESUMO

Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

5.
J Med Genet ; 56(9): 629-638, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31129566

RESUMO

BACKGROUND: Pathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease. METHODS: Reported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features. RESULTS: Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. CONCLUSION: These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.

6.
Eur J Med Genet ; 62(5): 397-404, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31085343

RESUMO

Personal genome screening (PGenS) is increasingly being offered as a screen for future health management, and to identify carrier status pertinent to reproductive decision-making. The aim of this study was therefore to explore the experience of individuals who undertook PGenS through the 2014 Sydney "Understand Your Genome (UYG)" event and a 2015 offer of PGenS by Australian biotechnology company Life Letters (LL). Eligible individuals were invited to participate by their clinical geneticist (UYG), or email from Director of LL. Semi-structured telephone interviews with 17 individuals were audio-recorded, transcribed, de-identified and analyzed by two coders using thematic analysis with an inductive approach. Nine participants had genetic/genomics expertise and eight were well-informed health and business professionals. Individual participant PGenS results included: an autosomal dominant condition not previously clinically identified (n = 1); carrier status for recessive condition(s) (n = 8); a number of disease-causing variants associated with an increased susceptibility to an inherited disorder (n = 7); variants of uncertain significance (n = 5); and a few pharmacogenomically-relevant variants (n = 4). The majority of participants described the importance of pre-test genetic counseling, information and/or consent (n = 12). Some barriers to uptake were identified, including scepticism by GPs (n = 6), colleagues (n = 3), and family members (n = 2), as well as privacy concerns (n = 4). Those without genetic/genomics expertise were mostly motivated to have testing by curiosity or interest in personal health (6/8), one seeking a diagnosis for an inherited medical condition and another for future health management. For many with genetic/genomics experience, the motivation was professional interest (8/9) and/or curiosity (5/9), without concern for personal health risk (4/9). On reflection, despite this initial motivation by the latter, the test result had unanticipated personal impact for some of this group, which changed over time (4/5). Several later recognized this, as health problems developed or family history was interrogated more closely. For all participants, disclosure of results to extended family members was limited. Most participants felt personal and family implications and communication (5/17) and/or expectations (3/17) should be addressed at the pre-test session, including more emphasis on residual risk and changes in interpretation with developing phenotypes. Those without genetics/genomics expertise highlighted the need for easy to understand pre-test information and/or an example report to be provided (7/8). These results are consistent with a need to develop more accessible resources, and more personalized counseling approaches to address expectations, dissemination of results, and preparedness for unexpected findings.


Assuntos
Triagem e Testes Direto ao Consumidor/métodos , Testes Genéticos/métodos , Competência em Informação , Adulto , Atitude , Triagem e Testes Direto ao Consumidor/psicologia , Triagem e Testes Direto ao Consumidor/normas , Feminino , Testes Genéticos/normas , Humanos , Masculino , Pessoa de Meia-Idade
8.
J Genet Couns ; 28(2): 240-250, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30964588

RESUMO

The study aimed to explore with consanguineous couples in Australia the acceptability and perceived utility of whole exome reproductive carrier screening for autosomal recessive and X-linked recessive conditions. Semi-structured interviews with 21 consanguineous couples were conducted prior to the offer of screening. Interviews were coded, and thematic analysis was informed by an inductive approach. Three major themes were identified: experiences and attitudes of Australian consanguineous couples, childhood genetic conditions and beliefs, and the perceived utility of genomic screening. All but one couple had previously sought genetic advice, and a large majority of couples were aware of childhood conditions within their family or community. Thirteen couples perceived consanguinity as increasing the risk of having affected children. Nine spoke of premarital screening programs routinely conducted in their countries of origin. All supported the concept and availability of genomic reproductive carrier screening. Hypothetically, if found to be carriers of a severe childhood disorder, 13 couples reported they would test a pregnancy, and 12 of whom would consider termination of pregnancy or pre-implantation genetic diagnosis. Four couples would not test a pregnancy and two were unsure. A majority of couples would communicate potential at-risk status to family members, although there were some caveats. Fourteen couples chose to have exome screening and reported that they would utilize the results with the goal of preventing childhood conditions. Of these couples, nine (64%) had an affected child but were aware that testing may reveal they were at risk for a child with a different condition and five (71%) without an affected child. While from diverse ethnic and backgrounds, all couples practiced a religion and all but one couple were recruited from the same clinical genetics unit, with a likely higher genetic literacy and bias towards accepting genetic testing. However, the choice made by all couples was reportedly made with consideration of their personal values, their current family situation, and exome testing issues, including fear of incidental findings and concerns about test reliability.

9.
Am J Hum Genet ; 104(3): 542-552, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827498

RESUMO

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

10.
Bioinformatics ; 35(1): 122-125, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561546

RESUMO

Motivation: Genome sequencing has had a remarkable impact on our ability to study the effects of human genetic variation, however, variant interpretation remains the major bottleneck. Understanding the potential impact of variants, including structural variants, requires extensive annotation from disparate sources of knowledge, and in silico prediction algorithms. Results: We introduce Seave, an intuitive web platform that enables all types of variants to be securely stored, annotated and filtered. Variants are annotated with allele frequencies and pathogenicity assessments from many popular databases and in silico pathogenicity prediction scores. Seave enables filtering of variants with specific inheritance patterns, including somatic variants, by quality, allele frequencies and gene lists which can be curated and saved. Seave was made for whole genome data and is capable of storing and querying copy number and structural variants. Availability and implementation: To demo Seave with public data, see https://www.seave.bio. Source code is available at http://code.seave.bio and extensive documentation is available at http://documentation.seave.bio. Seave can be locally installed on an Apache server with PHP and MySQL, or we provide an Amazon Machine Image for quick deployment. For commercial and clinical diagnostic licensing, contact the corresponding author. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Genoma Humano , Genômica/métodos , Internet , Software , Algoritmos , Biologia Computacional , Frequência do Gene , Variação Genética , Humanos
11.
Am J Hum Genet ; 104(1): 164-178, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30580808

RESUMO

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.


Assuntos
Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Mutação , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Face/anormalidades , Feminino , Deformidades Congênitas da Mão/genética , Humanos , Masculino , Micrognatismo/genética , Pescoço/anormalidades , Síndrome
12.
Hum Mutat ; 40(4): 374-379, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30556619

RESUMO

Rapid advances in genomic technologies have facilitated the identification pathogenic variants causing human disease. We report siblings with developmental and epileptic encephalopathy due to a novel, shared heterozygous pathogenic 13 bp duplication in SYNGAP1 (c.435_447dup, p.(L150Vfs*6)) that was identified by whole genome sequencing (WGS). The pathogenic variant had escaped earlier detection via two methodologies: whole exome sequencing and high-depth targeted sequencing. Both technologies had produced reads carrying the variant, however, they were either not aligned due to the size of the insertion or aligned to multiple major histocompatibility complex (MHC) regions in the hg19 reference genome, making the critical reads unavailable for variant calling. The WGS pipeline followed different protocols, including alignment of reads to the GRCh37 reference genome, which lacks the additional MHC contigs. Our findings highlight the benefit of using orthogonal clinical bioinformatic pipelines and all relevant inheritance patterns to re-analyze genomic data in undiagnosed patients.

14.
Am J Med Genet A ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30302899

RESUMO

Schaaf-Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader-Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2. This cohort includes 43 individuals that have been reported previously, as well as 35 newly identified individuals with confirmed pathogenic genetic variants. We emphasize that intellectual disability/developmental delay, autism spectrum disorder, neonatal hypotonia, infantile feeding problems, and distal joint contractures are the most consistently shared features of patients with SYS. Our results also indicate that there is a marked prevalence of infantile respiratory distress, gastroesophageal reflux, chronic constipation, skeletal abnormalities, sleep apnea, and temperature instability. While there are many shared features, patients with SYS are characterized by a wide phenotypic spectrum, including a variable degree of intellectual disability, language development, and motor milestones. Our results indicate that the variation in phenotypic severity may depend on the specific location of the truncating mutation, suggestive of a genotype-phenotype association. This evidence may be useful in both prenatal and pediatric genetic counseling.

15.
Fam Cancer ; 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30251170

RESUMO

The inclusion of polygenic risk scores in breast cancer risk prediction models provides a more personalised and accurate prediction of breast cancer risk for women with and without breast cancer, who would otherwise receive negative results from traditional testing of moderate- and high-risk genes. This study aimed to develop, and pilot test a leaflet with a sample of women participating in a large prospective cohort study. The leaflet aimed to provide information about polygenic risk to assist women to decide whether or not to learn results from genomic testing for common risk variants associated with breast cancer risk. A prototype of the leaflet was developed based on published literature and with the expertise from a multidisciplinary team. The acceptability of the leaflet was assessed by self-report questionnaire among 29 women participating in the prospective cohort study. More than 80% participants stated that the leaflet was clear, informative and easy to understand and increased their understanding of polygenic risk information. While low to moderate levels of distress/worry were reported around implications of the test results for the next generation, 71% felt reassured and agreed that the information provided in the leaflet had helped them cope. Pilot-test results indicate the leaflet is acceptable to the participants and the revised leaflet can be used as an information tool for women undergoing genomic testing. This educational leaflet will become a useful information source to meet the information needs of women undergoing genomic testing.

16.
J Genet Couns ; 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30187264

RESUMO

The study aimed to explore with consanguineous couples in Australia the acceptability and perceived utility of whole exome reproductive carrier screening for autosomal recessive and X-linked recessive conditions. Semi-structured interviews with 21 consanguineous couples were conducted prior to the offer of screening. Interviews were coded, and thematic analysis was informed by an inductive approach. Three major themes were identified: experiences and attitudes of Australian consanguineous couples, childhood genetic conditions and beliefs, and the perceived utility of genomic screening. All but one couple had previously sought genetic advice, and a large majority of couples were aware of childhood conditions within their family or community. Thirteen couples perceived consanguinity as increasing the risk of having affected children. Nine spoke of premarital screening programs routinely conducted in their countries of origin. All supported the concept and availability of genomic reproductive carrier screening. Hypothetically, if found to be carriers of a severe childhood disorder, 13 couples reported they would test a pregnancy, and 12 of whom would consider termination of pregnancy or pre-implantation genetic diagnosis. Four couples would not test a pregnancy and two were unsure. A majority of couples would communicate potential at-risk status to family members, although there were some caveats. Fourteen couples chose to have exome screening and reported that they would utilize the results with the goal of preventing childhood conditions. Of these couples, nine (64%) had an affected child but were aware that testing may reveal they were at risk for a child with a different condition and five (71%) without an affected child. While from diverse ethnic and backgrounds, all couples practiced a religion and all but one couple were recruited from the same clinical genetics unit, with a likely higher genetic literacy and bias towards accepting genetic testing. However, the choice made by all couples was reportedly made with consideration of their personal values, their current family situation, and exome testing issues, including fear of incidental findings and concerns about test reliability.

17.
Nat Genet ; 50(10): 1442-1451, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224647

RESUMO

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

18.
Cerebellum ; 2018 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-30078120

RESUMO

Genetic testing strategies such as next-generation sequencing (NGS) panels and whole genome sequencing (WGS) can be applied to the hereditary cerebellar ataxias (HCAs), but their exact role in the diagnostic pathway is unclear. We aim to determine the yield from genetic testing strategies and the genetic and phenotypic spectrum of HCA in Australia by analysing real-world data. We performed a retrospective review on 87 HCA cases referred to the Neurogenetics Clinic at the Royal North Shore Hospital, Sydney, Australia. Probands underwent triplet repeat expansion testing; those that tested negative had NGS-targeted panels and WGS testing when available. In our sample, 58.6% were male (51/87), with an average age at onset of 37.1 years. Individuals with sequencing variants had a prolonged duration of illness compared to those with a triplet repeat expansion. The detection rate in probands for routine repeat expansion panels was 13.8% (11/80). NGS-targeted panels yielded a further 11 individuals (11/32, 34.4%), with WGS yielding 1 more diagnosis (1/3, 33.3%). NGS panels and WGS improved the overall diagnostic rate to 28.8% (23/80) in 14 known HCA loci. The genetic findings included novel variants in ANO10, CACNA1A, PRKCG and SPG7. Our findings highlight the genetic heterogeneity of HCAs and support the use of NGS approaches for individuals who were negative on repeat expansion testing. In comparison to repeat disorders, individuals with sequencing variants may have a prolonged duration of illness, consistent with slower progression of disease.

19.
Genet Med ; 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29961766

RESUMO

PURPOSE: To provide proof of concept by broadening preconception screening beyond targeted testing to inform reproductive risk in consanguineous couples. METHODS: Consanguineous couples were screened for autosomal recessive and X-linked disorders using the TruSight One panel of 4,813 genes associated with human disease. RESULTS: We recruited 22 couples, of whom 15 elected to have sequencing. We found four couples to be at risk of autosomal recessive disorders, including one with a child affected by Poretti-Boltshauser syndrome (a diagnosis not made prior to the study) and another previously known to carry a ß-globin variant. Two couples were found to carry variants unrelated to known family history. These variants were in the genes C5orf42 (associated with Joubert syndrome and orofaciodigital syndrome) and GYS2 (associated with glycogen synthase deficiency). One known variant was not detected-a single exon deletion in FAM20C. We would not expect to identify this variant with the methodology employed. Of the four variants identified, only the ß-globin variant would have been found using available commercial preconception screening panels. CONCLUSION: Preconception screening of consanguineous couples for recessive and X-linked disorders using genomic sequencing is practicable, and is likely to detect many more at-risk couples than any targeted panel could achieve. A couples-based approach greatly reduces the associated analysis and counselling burden.

20.
Mol Syndromol ; 9(3): 149-153, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29928180

RESUMO

Crouzon syndrome (CS) and Beare-Stevenson syndrome (BSS) are craniosynostosis syndromes caused by mutations in the fibroblast growth factor 2 (FGFR2) gene. CS is more common (1 in 60,000 live births) than BSS, where fewer than 20 individuals have been reported. The cardinal features of BSS are craniosynostosis, cutis gyrata, acanthosis nigricans, skin furrows, skin tags, anogenital anomalies, and a prominent umbilical stump. Previously described individuals with BSS have typically had mutations in exon 11 of FGFR2. Here, we present 2 patients with CS who have significant skin manifestations and some phenotypic overlap with BSS. De novo mutations in exon 8 of FGFR2 were identified in both; one is a mutation (c.799T>C; p.Ser267Pro) previously identified in individuals with CS and the other a novel in-frame deletion (c.820_824delinsTT; p.Val274_Glu275delinsLeu). No mutations in exon 11 of FGFR2, where previously reported BSS mutations have been located, were identified. This case expands the phenotypic spectrum of CS and highlights the overlap between conditions caused by mutations in FGFR2.

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