129 research outputs found
Genome sequencing in families with congenital limb malformations
The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-021-02295-y
CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration
SummaryNeurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans
Characterization of greater middle eastern genetic variation for enhanced disease gene discovery
The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics
A new concept of skeletal dysplasias
The skeletal dysplasias form a large group of hereditary disorders characterized by abnormal growth and malformations of bone and cartilage. The clinical severity ranges from mildly affected short stature to lethal forms. Spranger classified approximately 200 different skeletal dysplasias in 1992, based on the clinical and radiographic features and the mode of genetic transmission. Etiopathogenesis of skeletal dysplasias is better documented now, with rapid accumulation of knowledge concerning defective genes and proteins causing this group of disorders. Mutations responsible for skeletal dysplasias may cause defects in the synthesis of structural proteins and in metabolic pathways, degradation of macromolecules, growth factors and receptors and transcription factors. Classifications by the International Working Group on Constitutional Diseases of Bone were based on the mutations in the same group gene taking into consideration the clinical and radiological findings (achondroplasia group, dysplasia with decreased bone density group and type 11 collagenopathies...). Clinical manifestations and radiological investigations are crucial for the differential diagnosis in skeletal dysplasias. However, prenatal diagnosis and postnatal definitive diagnosis are most often achieved by molecular analysis of the patient. Therefore, these groups of disorders require management by a multidisciplinary team of specialists, including pediatricians, genetic specialists, orthopedists and psychiatrists
Short trunk stature, brachydactyly, and platyspondyly in three sibs: A new form of brachyolmia or a new skeletal dysplasia?
We present a 27-year-old girl with short trunk stature, generalized rectangular platyspondyly and strike precocious calcification of costal cartilage. She had also brachydactyly, small nails, strabismus and delay of menarche. Her 16-year-old sister had also short trunk stature with severe kyphoscoliosis, hearing loss, brachydactyly, platyspondyly and mild precocious calcification of costal cartilages. Their 12-year-old brother had short trunk stature, kyphoscoliosis, brachydactyly, and platyspondyly but did not show precocious calcification of costal cartilage. The patients shared the following features: short trunk stature, brachydactyly, severe rectangular platyspondyly, broad and short femoral necks and hypoplasia of the ileum. In addition, the older sister had strike precocious calcification of costal cartilage while her sister and brother had severe kyphoscoliosis. Although short trunk stature and severe rectangular platyspondyly without significant epiphyseal or metaphyseal changes were in favor of Hobaek type brachyolmia, this diagnosis was not considered, both because, there were no specific radiological findings of this syndrome, such as elongated vertebral bodies extending beyond the pedicles laterally and all of the patients had brachydactyly which was not present in Hobaek type brachyolmia. The parents were healthy and first cousins signifying autosomal recessive inheritance. We considered that the patients couldbe affected by a new distinct autosomal recessive type brachyolmia or a new skeletal dysplasia. (C) 2003 Wiley-Liss, Inc
Thyroid dysfunction in children with Down's syndrome
Thyroid function tests were carried out on 320 children with Down's syndrome aged between 5 d and 10 y. Thyroid function was normal in 230 patients (71.9%) and abnormal in 90 (28.1%). Six patients (1.8%) had primary congenital hypothyroidism, one patient had acquired hypothyroidism and two had transient hyperthyrotropinaemia of the newborn. Sixteen of the remaining 81 patients (25.3%) had compensated hypothyroidism with increased thyroid-stimulating hormone (TSH) levels (11-20 mU l(-1)). Their T-4 levels were found to be either normal or close to the lower limit of normal. These cases were started on thyroxine therapy. Sixty-five of the 81 patients had a mild compensated hypothyroidism with mild TSH elevation (6-10 mU l(-1)). None of the patients had hyperthyroidism. The antithyroid antibodies were positive in the acquired hypothyroidism case
Spondyloenchondrodysplasia: Clinical variability in three cases
Spondyloenchondrodysplasia is a very rare skeletal dysplasia in which multiple enchondromata exist in the metaphyses of the long bones with platyspondyly. We present three patients (two of them are sibs) with spondyloenchondrodysplasia. The first patient was a 10-year-old boy, who had short stature and enchondromatous-like lesions in the metaphyses of the long bones and platyspondyly on radiography. His older sister (21-years old) had received growth hormone therapy 12 years earlier due to short stature, and her radiological findings were similar but milder than her brother. Both the sibs had normal intelligence and no calcification of the basal ganglia. The third patient was a 6-year-old boy who had short stature, mental retardation, enchondromatous-like lesions in the metaphyses of the long bones and platyspondyly. His cranial BT showed calcification of basal ganglia. The findings of the two sibs in the first family were compatible with spondyloenchondrodysplasia. The difference in clinical severity between the siblings shows the variability within the family. The third case with mental retardation and the presence of intracranial calcifications is compatible with spondyloenchondrodysplasia with basal ganglia calcification. In conclusion, we suggest that family screening and cranial imaging for the presence of intracranial calcifications should be considered in every patient with the diagnosis of spondyloenchondrodysplasia. (C) 2004 Wiley-Liss, Inc
Response to Kouwenberg et al. "Recognizable Phenotype With Common Occurrence of Microcephaly, Psychomotor Retardation, But No Spontaneous Bone Fractures in ARCL2B Due to PYCR1 Mutations"
Linear scleroderma en Coup de Sabre and brain calcification: Is there a pathogenic relationship?
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