ABSTRACT
Pituitary hormone deficiency occurs in â¼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.
Subject(s)
High-Throughput Screening Assays/methods , Hypopituitarism/pathology , Mutation , Pituitary Hormones/deficiency , RNA Splicing/genetics , Transcription Factor Pit-1/genetics , Adolescent , Adult , Child , Child, Preschool , Humans , Hypopituitarism/etiology , Hypopituitarism/metabolism , Male , PedigreeABSTRACT
As we continue to understand more about the complex mechanism of growth, a plethora of novel therapies have recently been developed that aim to address barriers and optimize efficacy. This review aims to explore these novel therapies and provide a succinct review based on the latest clinical studies in order to introduce clinicians to therapies that will soon constitute the future in the field of short stature. Conclusion: The review focuses on long-acting growth hormone formulations, a novel growth hormone oral secretagogue, novel treatments for children with achondroplasia, and targeted therapies for rare forms of skeletal dysplasias. What is Known: ⢠Recombinant human growth hormone has been the mainstay of treatment for children with short stature for years. ⢠Such therapy is not always effective based on the underlying diagnosis (e.g achondroplasia, Turner syndrome). Compliance with daily injections is challenging and can directly affect efficacy. What is New: ⢠Recent development of long-acting growth hormone regimens and oral secretagogues can overcome some of these barriers, however several limitations need to be taken into consideration. ⢠Newer therapies for achondroplasia, and other rare forms of skeletal dysplasias introduce us to a new era of targeted therapies for children with short stature. Clinicians ought to be aware of pitfalls and caveats before introducing these novel therapies to every day practice.
Subject(s)
Achondroplasia , Human Growth Hormone , Turner Syndrome , Child , Humans , Growth Disorders/drug therapy , Human Growth Hormone/therapeutic use , Growth Hormone/therapeutic use , Achondroplasia/drug therapyABSTRACT
BACKGROUND & AIMS: Two patients with homozygous mutations in PDX1 presented with pancreatic agenesis, chronic diarrhea, and poor weight gain, the causes of which were not identified through routine clinical testing. We aimed to perform a deep analysis of the stomach and intestine using organoids derived from induced pluripotent stem cells from PDX1188delC/188delC patients. METHODS: Gastric fundic, antral, and duodenal organoids were generated using induced pluripotent stem cell lines from a PDX1188delC/188delC patient and an isogenic induced pluripotent stem cell line where the PDX1 point mutation was corrected. RESULTS: Patient-derived PDX1188delC/188delC antral organoids exhibited an intestinal phenotype, whereas intestinal organoids underwent gastric metaplasia with significant reduction in enteroendocrine cells. This prompted a re-examination of gastric and intestinal biopsy specimens from both PDX1188delC/188delC patients, which recapitulated the organoid phenotypes. Moreover, antral biopsy specimens also showed increased parietal cells and lacked G cells, suggesting loss of antral identity. All organoid pathologies were reversed upon CRISPR-mediated correction of the mutation. CONCLUSIONS: These patients will now be monitored for the progression of metaplasia and gastrointestinal complications that might be related to the reduced gastric and intestinal endocrine cells. This study demonstrates the utility of organoids in diagnosing uncovered pathologies.
Subject(s)
Induced Pluripotent Stem Cells , Organoids , Cell Differentiation , Humans , Induced Pluripotent Stem Cells/metabolism , Metaplasia/metabolism , Mutation , Organoids/metabolism , StomachABSTRACT
BACKGROUND: Collagen X biomarker (CXM) is a novel biomarker of linear growth velocity. We investigated whether CXM correlated with measured growth velocity in children with impaired kidney function. METHODS: We used data from children aged 2 through 16 years old enrolled in the Chronic Kidney Disease in Children (CKiD) study. We assessed the association between CXM level and growth velocity based on height measurements obtained at study visits using linear regression models constructed separately by sex, with and without adjustment for CKD covariates. Linear mixed-effects models were used to capture the between-individual and within-individual CXM changes over time associated with concomitant changes in growth velocity from baseline through follow-up. RESULTS: A total of 967 serum samples from 209 participants were assayed for CXM. CXM correlated more strongly in females compared to male participants. After adjustment for growth velocity and CKD covariates, only proteinuria in male participants affected CXM levels. Finally, we quantified the between- and within-participant associations between CXM level and growth velocity. A between-participant increase of 24% and 15% in CXM level in females and males, respectively, correlated with a 1 cm/year higher growth velocity. Within an individual participant, on average, 28% and 13% increases in CXM values in females and males, respectively, correlated with a 1 cm/year change in measured growth. CONCLUSIONS: CXM measurement is potentially a valuable aid for monitoring growth in pediatric CKD. However, future research, including studies of CXM metabolism, is needed to clarify whether CXM can be a surrogate of growth in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.
Subject(s)
Renal Insufficiency, Chronic , Female , Humans , Child , Male , Adolescent , Renal Insufficiency, Chronic/diagnosis , Biomarkers , Collagen , Proteinuria/etiologyABSTRACT
The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGF binding protein-3 (IGFBP-3), pregnancy-associated plasma protein A (PAPP-A2), IGF-II and IGFBP-5 in 838 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated single nucleotide polymorphisms near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger causal relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.
Subject(s)
Body Height/genetics , Growth Hormone/genetics , Insulin-Like Growth Factor Binding Protein 3/genetics , Insulin-Like Growth Factor Binding Protein 5/genetics , Insulin-Like Growth Factor I/genetics , Adolescent , Birth Weight/genetics , Child , Child, Preschool , Female , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor Binding Protein 5/blood , Insulin-Like Growth Factor II/genetics , Male , Mendelian Randomization Analysis , Pregnancy-Associated Plasma Protein-A/genetics , Sitting PositionABSTRACT
VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.
Subject(s)
Intellectual Disability/genetics , Muscle Hypotonia/genetics , Neurodevelopmental Disorders/genetics , Neurons/metabolism , Synapses/metabolism , Vesicle-Associated Membrane Protein 2/genetics , Adolescent , Autistic Disorder/genetics , Autistic Disorder/metabolism , Brain/diagnostic imaging , Child , Child, Preschool , Epilepsy/metabolism , Exocytosis , Female , Heterozygote , Humans , Lipids/chemistry , Magnetic Resonance Imaging , Male , Membrane Fusion , Movement Disorders/genetics , Mutation , Neurodevelopmental Disorders/metabolism , Neurotransmitter Agents/metabolism , Phenotype , Protein Domains , R-SNARE Proteins/metabolism , Vesicle-Associated Membrane Protein 2/physiologyABSTRACT
By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.
Subject(s)
Craniofacial Abnormalities/genetics , Developmental Disabilities/genetics , Dwarfism/genetics , Genetic Variation , Intellectual Disability/genetics , Jumonji Domain-Containing Histone Demethylases/genetics , Musculoskeletal Abnormalities/genetics , Body Height , Child , Exome , Face , Female , Genetic Association Studies , Germ-Line Mutation , Haploinsufficiency , Histones/chemistry , Humans , Male , Mutation, Missense , PhenotypeABSTRACT
Aggrecan is a proteoglycan within the physeal and articular cartilage. Aggrecan deficiency, due to heterozygous mutations in the ACAN gene, causes dominantly inherited short stature and, in many patients, early-onset osteoarthritis and degenerative disc disease. We aimed to further characterize this phenotypic spectrum with an emphasis on musculoskeletal health. Twenty-two individuals from nine families were enrolled. Histories and examinations focused on joint health, gait analysis, joint specific patient reported outcomes, and imaging studies were performed. All patients had dominantly inherited short stature, with the exception of a de novo mutation. Short stature was worse in adults versus children (median height -3.05 SD vs. -2.25 SD). ACAN mutations were not always associated with bone age advancement (median advancement +1.1 years, range 0 to +2 years). Children had subtle disproportionality and clinically silent joint disease-25% with osteochondritis dissecans (OD). Adults had a high prevalence of joint symptomatology-decline in knee function, disability from spinal complaints, and lower physical activity on outcome measures. Osteoarthritis (OA) and OD was detected in 90% of adults, and orthopedic surgeries were reported in 60%. Aggrecan deficiency leads to short stature with progressive decline in height SD, mild skeletal dysplasia, and increasing prevalence of joint pathology over time. Optimal musculoskeletal health and quality of life can be attained with timely identification of pathology and intervention.
Subject(s)
Dwarfism , Osteoarthritis , Aggrecans/genetics , Dwarfism/genetics , Heterozygote , Humans , Phenotype , Quality of LifeABSTRACT
Patients with rare homozygous mutations in signal transducer and activator of transcription 5B (STAT5B) develop immunodeficiency resulting in chronic eczema, chronic infections, autoimmunity, and chronic lung disease. STAT5B-deficient patients are typically diagnosed in the teenage years, limiting our understanding of the development of associated phenotypic immune abnormalities. We report the first detailed chronological account of post-natal immune dysfunction associated with STAT5B deficiency in humans. Annual immunophenotyping of three siblings carrying a novel homozygous nonsense mutation in STAT5B was carried out over 4 years between the ages of 7 months to 8 years. All three siblings demonstrated consistent B cell hyperactivity including elevated IgE levels and autoantibody production, associated with diagnoses of atopy and autoimmunity. Total T cell levels in each sibling remained normal, with regulatory T cells decreasing in the oldest sibling. Interestingly, a skewing toward memory T cells was identified, with the greatest changes in CD8+ effector memory T cells. These results suggest an importance of STAT5B in B cell function and naïve versus memory T cell survival. Progressive dysregulation of FOXP3+ regulatory T cells and CD8+ memory T cell subsets reveal a crucial role of STAT5B in T cell homeostasis. The early diagnosis and focused immune evaluations of these three young STAT5B-deficient siblings support an important role of STAT5B in adaptive immune development and function.
Subject(s)
Adaptive Immunity/genetics , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , STAT5 Transcription Factor/deficiency , Siblings , Autoimmunity , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Biomarkers , Cell Line , Consanguinity , Disease Management , Disease Susceptibility , Genetic Association Studies , Homozygote , Humans , Infant , Male , Memory T Cells/immunology , Memory T Cells/metabolism , Mutation , Phenotype , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Exome SequencingABSTRACT
OBJECTIVE: To determine if the racial/ethnic inequity in growth hormone (GH) use is due to differences in GH stimulation testing and/or prescribing patterns in children referred for endocrine evaluation of short stature. STUDY DESIGN: Retrospective chart review was performed including children aged 2-16 years, height z-score of ≤-1.5, and of non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic race/ethnicity, referred for endocrine growth evaluation between January 2012 and December 2019. RESULTS: This study included 7425 children (5905 NHW, 800 NHB, and 720 Hispanic). GH stimulation testing was performed in 992, and 576 were prescribed GH. NHW children were 1.4 (95% CI, 1.04-1.8) times more likely than NHB children and 1.7 (95% CI, 1.2-2.2) times more likely than Hispanic children to undergo GH stimulation testing. GH-treated NHB children had (1) a lower median peak GH concentration when compared with NHW (P = .02) and Hispanic (P = .08) children (NHB 4.7 ng/mL [95% CI, 1.2-8.3 ng/mL] ng/mL, NHW 7.2 ng/mL [95% CI, 4.9-9.7 ng/mL], Hispanic 7.1 ng/mL [95% CI, 4.3-11.9 ng/mL]); (2) lower median height z-scores than NHW (P = .01) but not Hispanic children (P = .5); and (3) a greater height deficit from midparental height when compared with NHW (P = .01) and Hispanic (P = .002) children. CONCLUSIONS: Racial and ethnic disparities exist in the evaluation and treatment of children with disordered growth. This likely results from both overinvestigation of NHW children as well as underinvestigation and undertreatment of children from minority communities. The evaluation and treatment of children with short stature should be determined by clinical concern alone, but this is not current practice.
Subject(s)
Black or African American , Growth Disorders/diagnosis , Healthcare Disparities/ethnology , Hispanic or Latino , Human Growth Hormone/deficiency , White People , Adolescent , Body Height , Child , Child, Preschool , Diagnostic Techniques, Endocrine , Female , Growth Disorders/ethnology , Growth Disorders/therapy , Humans , Male , Practice Patterns, Physicians' , Retrospective StudiesABSTRACT
PURPOSE: Clinicians and researchers must contextualize a patient's genetic variants against population-based references with detailed phenotyping. We sought to establish globally scalable technology, policy, and procedures for sharing biosamples and associated genomic and phenotypic data on broadly consented cohorts, across sites of care. METHODS: Three of the nation's leading children's hospitals launched the Genomic Research and Innovation Network (GRIN), with federated information technology infrastructure, harmonized biobanking protocols, and material transfer agreements. Pilot studies in epilepsy and short stature were completed to design and test the collaboration model. RESULTS: Harmonized, broadly consented institutional review board (IRB) protocols were approved and used for biobank enrollment, creating ever-expanding, compatible biobanks. An open source federated query infrastructure was established over genotype-phenotype databases at the three hospitals. Investigators securely access the GRIN platform for prep to research queries, receiving aggregate counts of patients with particular phenotypes or genotypes in each biobank. With proper approvals, de-identified data is exported to a shared analytic workspace. Investigators at all sites enthusiastically collaborated on the pilot studies, resulting in multiple publications. Investigators have also begun to successfully utilize the infrastructure for grant applications. CONCLUSIONS: The GRIN collaboration establishes the technology, policy, and procedures for a scalable genomic research network.
Subject(s)
Data Management/methods , Electronic Data Processing/methods , Information Storage and Retrieval/methods , Biological Specimen Banks/standards , Biomedical Research/methods , Databases, Factual , Databases, Genetic , Ethics Committees, Research , Genomics/methods , Humans , Information Dissemination , Research PersonnelABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
PURPOSE: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.
Subject(s)
Intellectual Disability , Megalencephaly , Neurodevelopmental Disorders , Child , Female , GATA Transcription Factors/genetics , Humans , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , Nucleosomes , Phenotype , Pregnancy , Repressor ProteinsABSTRACT
Early diagnosis of Turner syndrome enhances care, but in routine practice, even within larger referral centers, diagnosis is delayed. Our study examines the utility of an electronic health record algorithm in identifying patients at high risk for Turner syndrome. Six percent of those identified had missed diagnoses of Turner syndrome.
Subject(s)
Algorithms , Electronic Health Records , Turner Syndrome/diagnosis , Adolescent , Child , Child, Preschool , Early Diagnosis , Female , HumansABSTRACT
OBJECTIVE: To report a novel mutation in GHR and to characterize a novel mechanism of nonclassical growth hormone insensitivity. CONTEXT: Laron syndrome (LS) is a well-described disorder of growth hormone insensitivity due to mutations in the growth hormone receptor (GHR) that leads to short stature. Biochemically, LS patients classically have elevated levels of growth hormone (GH), but low levels of insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-3 and GH binding protein (GHBP). DESIGN: Case presentation with in vitro functional studies. PATIENTS: A young male Caucasian child with short stature was found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP. MEASUREMENTS: Growth hormone stimulation tests revealed baseline GH level of 20.9 µg/L and maximum stimulated GH level of 52.7 µg/L and GHBP level of 4868 pmol/L. GHR gene sequencing revealed a novel heterozygous nonsense mutation (c.800G > A, p.Trp267*) in the transmembrane domain of the receptor. Immunoblot analysis of transfected GHR p.Trp267* in HEK293 revealed inhibition of GH-induced STAT5 signalling that was overcome with increasing doses of recombinant human GH. RESULTS: Using an in vitro model, we show that elevated levels of GHBP inhibit the action of GH. Furthermore, our studies demonstrate that this inhibition by GHBP can be overcome by increasing doses of recombinant human GH. CONCLUSIONS: To our knowledge, this is the first study to demonstrate in vitro that elevated levels of GHBP attenuate the effect of GH and inhibit GH-induced signalling, thereby leading to short stature. Though this inhibition was overcome in vitro with supraphysiologic doses of GH, significantly above endogenously available GH, it remains to be seen whether such an effect can be replicated in vivo.
Subject(s)
Human Growth Hormone , Receptors, Somatotropin , Carrier Proteins/genetics , Child , Codon, Nonsense/genetics , Growth Hormone , HEK293 Cells , Human Growth Hormone/genetics , Humans , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Male , Receptors, Somatotropin/geneticsABSTRACT
Whole-exome sequencing has enabled new approaches for discovering genes associated with monogenic disorders. One such approach is gene-based burden testing, in which the aggregate frequency of "qualifying variants" is compared between case and control subjects for each gene. Despite substantial successes of this approach, the genetic causes for many monogenic disorders remain unknown or only partially known. It is possible that particular genetic architectures lower rates of discovery, but the influence of these factors on power has not been rigorously evaluated. Here, we leverage large-scale exome-sequencing data to create an empirically based simulation framework to evaluate the impact of key parameters (background variation rates, locus heterogeneity, mode of inheritance, penetrance) on power in gene-based burden tests in the context of monogenic disorders. Our results demonstrate that across genes, there is a wide range in sample sizes needed to achieve power due to differences in the background rate of rare variants in each gene. Increasing locus heterogeneity results in rapid increases in sample sizes needed to achieve adequate power, particularly when individual genes contribute to less than 5% of cases under a dominant model. Interestingly, incomplete penetrance as low as 10% had little effect on power due to the low prevalence of monogenic disorders. Our results suggest that moderate incomplete penetrance is not an obstacle in this gene-based burden testing approach but that dominant disorders with high locus heterogeneity will require large sample sizes. Our simulations also provide guidance on sample size needs and inform study design under various genetic architectures.
Subject(s)
Genetic Association Studies/methods , Genetic Diseases, Inborn/genetics , Models, Genetic , Exome/genetics , Genes, Recessive/genetics , Humans , Penetrance , Sample Size , Sequence Analysis, DNAABSTRACT
Whole-exome sequencing (WES) is increasingly being utilized to diagnose individuals with undiagnosed disorders. Developmental delay and short stature are common clinical indications for WES. We performed WES in three families, using proband-parent trios and two additional affected siblings. We identified a syndrome due to an autosomal-recessively inherited deficiency of transketolase, encoded by TKT, on chromosome 3p21. Our series includes three families with a total of five affected individuals, ranging in age from 4 to 25 years. Two families of Ashkenazi Jewish ancestry were homozygous for an 18 base pair in-frame insertion in TKT. The third family was compound heterozygous for nonsense and missense variants in TKT. All affected individuals had short stature and were developmentally delayed. Congenital heart defects were noted in four of the five affected individuals, and there was a history of chronic diarrhea and cataracts in the older individuals with the homozygous 18 base pair insertion. Enzymatic testing confirmed significantly reduced transketolase activity. Elevated urinary excretion of erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates was detected, as well as elevated amounts of erythritol, arabitol, and ribitol in the plasma of affected individuals. Transketolase deficiency reduces NADPH synthesis and nucleic acid synthesis and cell division and could explain the problems with growth. NADPH is also critical for maintaining cerebral glutathione, which might contribute to the neurodevelopmental delays. Transketolase deficiency is one of a growing list of inborn errors of metabolism in the non-oxidative part of the pentose phosphate pathway.
Subject(s)
Developmental Disabilities/etiology , Dwarfism/etiology , Heart Defects, Congenital/etiology , Mutation/genetics , Transketolase/genetics , Adult , Child , Child, Preschool , Developmental Disabilities/metabolism , Developmental Disabilities/pathology , Dwarfism/metabolism , Dwarfism/pathology , Female , Glutathione/metabolism , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology , Humans , Male , NADP/metabolism , Pedigree , Syndrome , Young AdultABSTRACT
OBJECTIVE: To perform a prospective genetic investigation using whole exome sequencing of a group of patients with syndromic short stature born small for gestational age of unknown cause. STUDY DESIGN: For whole exome sequencing analysis, we selected 44 children born small for gestational age with persistent short stature, and additional features, such as dysmorphic face, major malformation, developmental delay, and/or intellectual disability. Seven patients had negative candidate gene testing based on clinical suspicion and 37 patients had syndromic conditions of unknown etiology. RESULTS: Of the 44 patients, 15 (34%) had pathogenic/likely pathogenic variants in genes already associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4, ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and POC1A (n = 1 each). Most of the genes found to be deleterious participate in fundamental cellular processes, such as cell replication and DNA repair. CONCLUSIONS: The rarity and heterogeneity of syndromic short stature make the clinical diagnosis difficult. Whole exome sequencing allows the diagnosis of previously undiagnosed patients with syndromic short stature.
Subject(s)
Dwarfism/genetics , Exome Sequencing , Abnormalities, Multiple/genetics , Actins/genetics , Adenosine Triphosphatases/genetics , Cell Cycle Proteins/genetics , Child , Cyclin-Dependent Kinase Inhibitor p57/genetics , Cytoskeletal Proteins/genetics , DNA-Binding Proteins/genetics , Histone-Lysine N-Methyltransferase/genetics , Humans , Infant, Small for Gestational Age , Kinesins/genetics , Male , Mutation , Myeloid-Lymphoid Leukemia Protein/genetics , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/genetics , Prospective Studies , Repressor Proteins/genetics , Transcriptional Elongation Factors/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
BACKGROUND/AIMS: The genetics of human height is a frequently studied and complex issue. However, there is limited genetic research of short stature. To uncover the subgroup of patients to have higher yield and to propose a simplified diagnostic algorithm in the next generation era. METHODS: This study included 114 Chinese children with height SDS ≤ -2.5 and unknown etiology from 2014 to 2015. Target/whole exome sequencing (referred as NGS) and chromosomal microarray analysis (CMA) were performed on the enrolled patients sequentially to identify potential genetic etiologies. The samples solved by NGS and CMA were retrospectively studied to evaluate the clinical pathway of the patients following a standard diagnostic algorithm. RESULTS: In total, a potential genetic etiology was identified in 41 (36%) patients: 38 by NGS (33.3%), two by CMA (1.8%), and an additional one by both (0.9%). There were 46 different variants in 29 genes and 2 pathogenic CNVs identified. The diagnostic yield was significantly higher in patients with facial dysmorphism or skeletal abnormalities than those without the corresponding phenotype (P=0.006 and P=0.009, respectively, Pearson's χ2 test). Retrospectively study the cohort indicate 83.3% patients eventually would be evaluated by NGS/CMA. CONCLUSION: This study confirms the utility of high-throughput molecular detection techniques for the etiological diagnosis of undiagnosed short stature and suggests that NGS could be used as a primary diagnostic strategy. Patients with facial dysmorphism and/or skeletal abnormalities are more likely to have a known genetic etiology. Moving NGS forward would simplified the diagnostic algorithm.