ABSTRACT
PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.
Subject(s)
Intellectual Disability , Phenotype , Humans , Adult , Intellectual Disability/genetics , Intellectual Disability/epidemiology , Male , Female , Middle Aged , Young Adult , Haploinsufficiency/genetics , Seizures/genetics , Seizures/epidemiology , Physicians , Adolescent , Facies , Abnormalities, Multiple , Bone Diseases, Developmental , Tooth AbnormalitiesABSTRACT
Inherited cardiovascular conditions are significant causes of sudden cardiac death in the young (SCDY), making their investigation using molecular autopsy and prevention a public health priority. However, the molecular autopsy data in Chinese population is lacking. The 5-year result (2017-2021) of molecular autopsy services provided for victims of SCDY (age 1-40 years) was reviewed. The outcome of family cascade genetic screening and clinical evaluation was reviewed. A literature review of case series reporting results of molecular autopsy on SCDY in 2016-2023 was conducted. Among the 41 decedents, 11 were found to carry 13 sudden cardiac death (SCD)-causative genetic variants. Likely pathogenic (LP) variants were identified in the DSP, TPM1, TTN, and SCN5A genes. Cascade genetic testing identified four family members with LP variants. One family member with familial TPM1 variant was found to have hypertrophic cardiomyopathy upon clinical evaluation. This study provided insight into the genetic profile of molecular autopsy in a Chinese cohort of SCDY. The detection of important SCD-causative variants through molecular autopsy has facilitated family cascade screening by targeted genetic testing and clinical evaluation of at-risk family members. A literature review of the current landscape of molecular autopsy in the investigation of SCDY was conducted.
ABSTRACT
Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A-affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at-risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty-seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype-phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision-making.
Subject(s)
Hemophilia A , Heterozygote , Humans , Hemophilia A/genetics , Hemophilia A/pathology , Hemophilia A/epidemiology , Female , Male , Adult , Mutation/genetics , Factor VIII/genetics , Retrospective Studies , Genetic Association Studies , PhenotypeABSTRACT
Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and SNP array study on amniotic fluid samples were normal. Whole exome sequencing (WES) was initiated further as the fetus had pericardial effusion of 1.2 mm, thickened myocardium over the right ventricular lateral wall and aberrant right subclavian artery. A detailed fetal echocardiogram also revealed persistent left superior vena cava and dilated coronary sinus at 20 weeks. From whole exome sequencing of the trio, a de novo heterozygous variant NM_005359.5(SMAD4): c.1499T>C (p.Ile500Thr) was detected. This pathogenic variant has been reported in the postnatal case cohort of Myhre syndrome. This condition is characterized by facial dysmorphism, intellectual disability, hearing loss, skeletal abnormalities and potential life threatening respiratory or cardiovascular manifestations. Termination of pregnancy was performed at 23 weeks. Small chins, pre-axial polydactyly, brachydactyly and clinodactyly were noted in the abortus. Ultrasound findings of increased nuchal translucency, thickened myocardium and pericardial effusion prompted further genetic evaluation for the prenatal diagnosis of Myhre syndrome by whole exome sequencing.
Subject(s)
Heart Defects, Congenital , Intellectual Disability , Pericardial Effusion , Pregnancy , Female , Humans , Adult , Intellectual Disability/diagnostic imaging , Intellectual Disability/genetics , Nuchal Translucency Measurement , Vena Cava, Superior , Prenatal Diagnosis , Ultrasonography, Prenatal , Smad4 Protein/geneticsABSTRACT
Strømme syndrome (MIM #243605) is a rare autosomal recessive ciliopathy resulting from compound heterozygous or homozygous pathogenic alterations in the CENPF gene (# 600236). Although there are a number of case reports featuring individuals with clinically compatible Strømme syndrome, only 13 affected individuals had molecular confirmation worldwide. Herein, we report a 24 years old Chinese gentleman with molecularly confirmed Strømme syndrome with compound heterozygous pathogenic nonsense variants in NM_016343.3(CENPF):c.436C > T, p.(Gln146*) and c.9280C > T, p.(Arg3094*). He presented with microcephaly, unilateral microphthalmia, single central upper incisor and bilateral preaxial polydactyly. To our knowledge, this is the first reported Chinese individual with molecularly confirmed Strømme syndrome.
Subject(s)
Eye Abnormalities , Microcephaly , China , Eye Abnormalities/diagnosis , Eye Abnormalities/genetics , Humans , Intestinal Atresia , Male , Microcephaly/diagnosis , Microcephaly/genetics , Microcephaly/pathology , Pedigree , PhenotypeABSTRACT
DeSanto-Shinawi syndrome (DESSH, OMIM #616708) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in the WAC gene. Affected individuals are characterized by neonatal hypotonia, developmental delay, intellectual disability, behavioral problems, and dysmorphism. Epilepsy is present in some of the patients with DESSH. By far, less than 30 affected individuals have been reported worldwide. Herein, we report a 9-year-old Chinese girl with molecularly substantiated DESSH with a de novo nonsense c. 1648C>T p.(Arg550*) variant identified in the WAC gene. Aside from developmental delay and the characteristic facial gestalt, our proband also exhibited tethered cord syndrome due to filar lipoma and left duplex kidney complicated with hydronephrosis, features not observed in any of the previously reported individuals with DESSH.
Subject(s)
Intellectual Disability , Neurodevelopmental Disorders , Face , Humans , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Muscle Hypotonia/genetics , PhenotypeABSTRACT
KBG syndrome (OMIM #148050) is an autosomal dominant neurodevelopmental disorder characterized by the presence of macrodontia of the permanent central upper incisors, characteristic facial features, delay in development, intellectual disability, short stature, and various skeletal abnormalities. Over 200 affected individuals have been described worldwide, though underdiagnosis is suspected because the characteristic features are variably present and affected individuals can have a mild phenotype. This case series provides a summary of the clinical and molecular characteristics of 10 Chinese KBG syndrome patients recruited from a single center. To our knowledge, this is the first case series for Chinese KBG patients. This case series aimed at exploring potential ethnicity-related variability in KBG syndrome.
Subject(s)
Abnormalities, Multiple , Bone Diseases, Developmental , Intellectual Disability , Tooth Abnormalities , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Bone Diseases, Developmental/diagnosis , Bone Diseases, Developmental/genetics , China/epidemiology , Comparative Genomic Hybridization , Facies , Humans , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Phenotype , Repressor Proteins/genetics , Tooth Abnormalities/diagnosis , Tooth Abnormalities/geneticsABSTRACT
CTNNB1-related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1-related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1-related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations.
Subject(s)
Microcephaly , Neurodevelopmental Disorders , China/epidemiology , Familial Exudative Vitreoretinopathies , Humans , Microcephaly/genetics , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/genetics , Phenotype , beta CateninABSTRACT
Beckwith Wiedemann Syndrome (BWS, OMIM 130650) is an imprinting disorder that may present antenatally with a constellation of sonographic features namely polyhydramnios, macrosomia, macroglossia, omphalocele, placental mesenchymal dysplasia, cardiomegaly, nephromegaly, fetal hydrops, and other rare anomalies. Paternal uniparental disomy in chromosome 11p15 imprinting region accounts for 20% of all BWS, and 8% among those were due to genome-wide paternal uniparental disomy (GWpUPD). GWpUPD is a rare condition and usually results in prenatal lethality. The 31 liveborns reported in the literature demonstrate female predominance in surviving GWpUPD. Here, we reported two prenatal cases which initially presented with features suggestive of BWS, which subsequently were confirmed to have GWpUPD. Further trio SNP genotyping analysis using SNP-based chromosomal microarray revealed androgenetic biparental chimera as the underlying cause. Finally, we highlighted the importance of recognizing GWpUPD as a possible cause in a fetus presenting with BWS phenotype, as it carried a different disease prognosis, tumor predisposition, manifestations of other imprinting disorders, and possibility in unmasking autosomal recessive disorders from the paternal alleles.
Subject(s)
Beckwith-Wiedemann Syndrome , Androgens , Beckwith-Wiedemann Syndrome/diagnosis , Beckwith-Wiedemann Syndrome/genetics , Chimera , DNA Methylation/genetics , Female , Fetus , Genomic Imprinting/genetics , Humans , Placenta , Pregnancy , Uniparental Disomy/geneticsABSTRACT
Variants of the diphthamide biosynthesis I (DPH1, OMIM*603527) are associated with developmental delay, short stature, and sparse hair syndrome (DEDSSH/DPH1 syndrome) (OMIM# 616901). Another name is Loucks-Innes syndrome. DPH1 syndrome is an ultrarare and severe neurodevelopmental disorder. Less than 20 patients were reported from different ethnicities. Here, we described the first Chinese adult with genetically confirmed DPH1 syndrome. We summarized previously reported patients in the literature and found that developmental delay, unusual skull shape, sparse hair, and facial dysmorphism were consistently present in all DPH1 syndrome patients. Dysplastic toenails and dental abnormalities are age-dependent characteristics of DPH1 syndrome. Our patient was the first reported patient with documented growth hormone deficiency. Dental and endocrine checkup should be considered in the routine follow-up of DPH1 syndrome patients.
Subject(s)
Developmental Disabilities/genetics , Dwarfism, Pituitary/genetics , Minor Histocompatibility Antigens/genetics , Neurodevelopmental Disorders/genetics , Tumor Suppressor Proteins/genetics , Adult , Developmental Disabilities/pathology , Dwarfism, Pituitary/pathology , Humans , Male , Musculoskeletal Abnormalities/diagnosis , Musculoskeletal Abnormalities/genetics , Musculoskeletal Abnormalities/pathology , Mutation/genetics , Neurodevelopmental Disorders/pathologyABSTRACT
Rubinstein-Taybi syndrome (RSTS, OMIM*180849) is a rare autosomal dominant disorder, characterized by distinctive facial features, short stature, broad and often angulated thumbs and halluces, with occasional congenital anomalies. Characteristic facial dysmorphic features include downslanting palpebral fissures, low hanging columella. RSTS is caused by pathogenic variants in two ubiquitously expressed and highly homologous genes, CREBBP (OMIM*600140) and EP300 (OMIM*600140). Clinical features were well reported especially in Caucasian ethnicity. We would like to report the clinical phenotype of RSTS in our Chinese population and highlight four novel mutations in CREBBP gene.
Subject(s)
CREB-Binding Protein/genetics , E1A-Associated p300 Protein/genetics , Genetic Predisposition to Disease , Rubinstein-Taybi Syndrome/genetics , Adolescent , Adult , Child , Child, Preschool , China/epidemiology , Female , Frameshift Mutation/genetics , Humans , Infant , Male , Middle Aged , Mutation, Missense/genetics , Phenotype , Rubinstein-Taybi Syndrome/epidemiology , Rubinstein-Taybi Syndrome/pathology , Young AdultABSTRACT
Mandibular hypoplasia, deafness, progeroid feature, and lipodystrophy syndrome (MDPL, MIM# 615381) is an extremely rare and recently recognized early adult onset of progeroid syndrome, with features of generalized lipodystrophy, dysmorphic features, telangiectasia, early onset hearing loss, insulin resistance, and dyslipidemia. Here, we present a 31-year-old Chinese woman with MDPL, harboring the recurrent pathogenic variant p.(Ser605del) in POLD1, illustrating the evolving manifestations of this premature aging disorder from infancy to adulthood.
Subject(s)
Abnormalities, Multiple/genetics , DNA Polymerase III/genetics , Lipodystrophy, Congenital Generalized/genetics , Micrognathism/genetics , Progeria/genetics , Adult , DNA Polymerase III/deficiency , Deafness/genetics , Disease Progression , Dyslipidemias/genetics , Female , Genes, Dominant , Humans , Insulin Resistance/genetics , Myopia/genetics , Syndrome , Telangiectasis/genetics , Thinness/geneticsABSTRACT
Coffin-Siris syndrome (CSS, MIM# 1359200) is a multisystem congenital disorder characterized by coarse facial features, hypoplasia of the fifth digits and nails, and intellectual disability. It is a genetically heterogeneous condition caused by pathogenic variants in genes encoding proteins of the BAF (BRG1-associated factors) chromatin modeling complex and its downstream transcriptional factor. To date over 220 CSS individuals with pathogenic variants found have been described in the literature. This case series reported 18 molecularly confirmed Chinese individuals (17 with ARIDIB (OMIM*614556) variants and one with SMARCB1 (OMIM*601607) variant) from 17 unrelated families in Hong Kong. The clinical features of these 18 Chinese CSS patients together with two previously reported Chinese patients with ARID1B variants were reviewed. Among the 19 Chinese patients with ARID1B variants, our data suggested a lower prevalence of feeding problem, autistic features, agenesis of corpus callosum (ACC) or partial/hypoplasia of corpus callosum, and sparse hair when compared with previous reports. There was appearing higher prevalence of digital hypoplasia. Digital hypoplasia was observed to become less noticeable with time in some patients. This report highlighted the age-dependent phenotypic presentation of CSS and ethnicity-related effect on ARID1B-CSS phenotype. Moreover, this series included the first family with molecularly confirmed maternal somatic mosaicism of ARID1B variant leading to familial CSS recurrence.
Subject(s)
Abnormalities, Multiple/genetics , DNA-Binding Proteins/genetics , Face/abnormalities , Genetic Predisposition to Disease , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Transcription Factors/genetics , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Child , Child, Preschool , Face/physiopathology , Female , Genotype , Hand Deformities, Congenital/physiopathology , Humans , Infant , Intellectual Disability/physiopathology , Male , Micrognathism/physiopathology , Neck/physiopathology , Phenotype , Young AdultABSTRACT
Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended.
Subject(s)
Abnormalities, Multiple/genetics , Dwarfism/genetics , Eye Abnormalities/genetics , Hyperostosis, Cortical, Congenital/genetics , Hypocalcemia/genetics , Receptors, Virus/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/physiopathology , Adult , China/epidemiology , Dwarfism/diagnosis , Dwarfism/epidemiology , Dwarfism/physiopathology , Eye Abnormalities/diagnosis , Eye Abnormalities/epidemiology , Eye Abnormalities/physiopathology , Female , Humans , Hyperostosis, Cortical, Congenital/diagnosis , Hyperostosis, Cortical, Congenital/epidemiology , Hyperostosis, Cortical, Congenital/physiopathology , Hypocalcemia/diagnosis , Hypocalcemia/epidemiology , Hypocalcemia/physiopathology , Male , Middle Aged , Phenotype , Twins/geneticsABSTRACT
Schuurs-Hoeijmakers syndrome (SHS) is a rare syndrome involving a de novo variant in the PACS1 gene on chromosome 11q13. There are 36 individuals published in the literature so far, mostly diagnosed postnatally (34/36) after recognizing the typical facial features co-occurring with developmental delay, intellectual disability, and multiple malformations. Herein, we present one prenatal and 15 postnatal cases with the recurrent heterozygous pathogenic variant NM_018026.3:c.607C>T p.(Arg203Trp) in the PACS1 gene detected by exome sequencing. These 16 cases were identified by mining Centogene and the Hong Kong clinical genetic service databases. Collectively, the 49 postnatally diagnosed individuals present with typical facial features and developmental delay, while the three prenatally diagnosed individuals present with multiple congenital anomalies. In the current study, the use of exome sequencing as an unbiased diagnostic tool aided the diagnosis of SHS (pre- and postnatally). The identification of additional cases with SHS add to the current understanding of the clinical phenotype associated with pathogenic PACS1 variants. Databases combining clinical and genetic information are helpful for the study of rare diseases.
Subject(s)
Abnormalities, Multiple/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Vesicular Transport Proteins/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Child , Developmental Disabilities/diagnosis , Developmental Disabilities/pathology , Female , Heterozygote , Humans , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Male , Phenotype , Prenatal Diagnosis/methods , Exome SequencingABSTRACT
OBJECTIVES: Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS. METHODS: We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS. RESULTS: We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non-specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%). CONCLUSIONS: These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non-specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.
Subject(s)
Abnormalities, Multiple/genetics , Face/abnormalities , Hematologic Diseases/genetics , Phenotype , Vestibular Diseases/genetics , Case-Control Studies , Child , Child, Preschool , Female , Humans , Male , Pregnancy , Ultrasonography, Prenatal/methods , Ultrasonography, Prenatal/statistics & numerical dataABSTRACT
CHARGE syndrome (CS) is a multiple congenital anomalies condition with the majority of cases caused by dominant loss-of-function mutations of the CHD7 gene. It is clinically characterized by coloboma of the eyes, heart defects, choanal atresia, retardation of growth and/or development, genital and/or urinary anomalies and ear malformations associated with deafness and vestibular disorder(s). This case series reported nine molecularly confirmed Chinese CS patients from nine unrelated families in Hong Kong. Clinical phenotype and facial features of these nine Chinese CS patients together with four previously reported Chinese patients were reviewed. Typical presentations like coloboma and choanal atresia were not universally present. The prevalence of choanal atresia in these Chinese CS patients was found to be significantly lower than that in previous cohorts of other ethnic groups. This report highlighted the existence of phenotypic variation of CS among different ethnicities and suggested that a high index of suspicion is necessary for diagnosis of CS in Chinese patients.
Subject(s)
CHARGE Syndrome/genetics , Choanal Atresia/genetics , Coloboma/genetics , DNA Helicases/genetics , DNA-Binding Proteins/genetics , CHARGE Syndrome/pathology , Child , Child, Preschool , China/epidemiology , Choanal Atresia/pathology , Coloboma/pathology , Female , Hong Kong/epidemiology , Humans , Infant , Male , Mutation , PhenotypeABSTRACT
Mowat-Wilson syndrome (MWS) is characterized clinically by a distinctive facial gestalt, intellectual disability, microcephaly, epilepsy, and nonobligatory congenital malformations such as Hirschsprung disease, urogenital anomalies, congenital heart disease, eye malformations. This article summarized the clinical features and molecular findings of 15 Chinese MWS patients. The results revealed a higher incidence of congenital heart disease in Chinese MWS patients compared to that previously reported in Caucasian cohorts, while the incidence of Hirschsprung disease and genitourinary malformation appeared to be lower. This suggests possible ethnicity-related modifying effects in the MWS phenotype.
Subject(s)
Heart Defects, Congenital/genetics , Hirschsprung Disease/genetics , Intellectual Disability/genetics , Microcephaly/genetics , Adolescent , Adult , Child , Child, Preschool , China/epidemiology , Facies , Female , Heart Defects, Congenital/complications , Heart Defects, Congenital/pathology , Hirschsprung Disease/complications , Hirschsprung Disease/pathology , Humans , Intellectual Disability/complications , Intellectual Disability/pathology , Male , Microcephaly/complications , Microcephaly/pathology , Repressor Proteins , Urogenital Neoplasms/complications , Urogenital Neoplasms/genetics , Urogenital Neoplasms/pathology , Young AdultABSTRACT
Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.
Subject(s)
E1A-Associated p300 Protein/genetics , Ethnicity/genetics , Face/abnormalities , Genetics, Population , Mutation , Rubinstein-Taybi Syndrome/epidemiology , Adolescent , Adult , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Female , Genetic Association Studies , Humans , Infant , International Agencies , Male , Middle Aged , Prognosis , Rubinstein-Taybi Syndrome/genetics , Rubinstein-Taybi Syndrome/pathology , Young AdultABSTRACT
BACKGROUND: Chromosomal microarray (CMA) has been shown to be cost-effective over karyotyping in invasive prenatal diagnosis for pregnancies with fetal ultrasound anomalies. Yet, information regarding preceding and subsequent tests must be considered as a whole before the true cost-effectiveness can emerge. Currently in Hong Kong, karyotyping is offered free as the standard prenatal test while genome-wide array comparative genome hybridization (aCGH), a form of CMA, is self-financed. A new algorithm was proposed to use aCGH following quantitative fluorescent polymerase chain reaction (QF-PCR) as primary test instead of karyotyping. This study aims to evaluate the cost-effectiveness of the proposed algorithm versus the current algorithm for prenatal diagnosis in Hong Kong. METHODS: Between November 2014 and February 2016, 129 pregnant women who required invasive prenatal diagnosis at two public hospitals in Hong Kong were prospectively recruited. The proposed algorithm was performed for all participants in this demonstration study. For the cost-effectiveness analysis, cost and outcome (diagnostic rate) data were compared with that of a hypothetical scenario representing the current algorithm. Further analysis was performed to incorporate women's willingness-to-pay for the aCGH test. Impact of government subsidies on the aCGH test was explored as a sensitivity analysis. RESULTS: The proposed algorithm dominated the current algorithm for prenatal diagnosis. Both algorithms were equally effective but the proposed algorithm was significantly cheaper (p ≤ 0.05). Taking into account women's willingness-to-pay for an aCGH test, the proposed algorithm was more effective and less costly than the current algorithm. When the government subsidy reaches 100%, the maximum number of diagnoses could be made. CONCLUSION: By switching to the proposed algorithm, cost saving can be achieved whilst maximizing the diagnostic rate for invasive prenatal diagnosis. It is recommended to implement aCGH as a primary test following QF-PCR to replace the majority of karyotyping for prenatal diagnosis in Hong Kong.