Abstract
Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands’ features.
Highlights
The advent of high-throughput sequencing led to the delineation of multiple syndromes
Our searches for more case subjects led to the identification of a total of 19 affected individuals from 10 families recruited in Algeria (AL), Lithuania (LT), Saudi Arabia (SA1–SA3), Singapore (SG), Tunisia (TU1, TU2), the United Kingdom (UK), and the United States of America (US) (Figure 2A)
Genetic variants associated with the complex phenotype of interest were uncovered through exome sequencing of the affected individuals and their healthy parents with the exception of SG.II.[4]
Summary
The advent of high-throughput sequencing led to the delineation of multiple syndromes. 116 The American Journal of Human Genetics 102, 116–132, January 4, 2018 cerebellar development They can be classified into four main categories depending on the origin of the defect.[4] First are disorders due to abnormal proliferation of neuronal and glial cells including brain under-growth (microcephaly) or overgrowth (megalencephaly). The last category regroups malformations of the mid-hindbrain with early anteroposterior and dorsoventral patterning defects This phenotypic heterogeneity is paralleled by molecular heterogeneity as more than 100 genes have been implicated to date.[4,5,6,7] The causative genes can be arranged into specific biological pathways (for instance synapse structure, cellular growth regulation, apoptosis, cell-fate specification, actin cytoskeleton, and microtubule assembly) that do not necessarily correlate with the type of malformations described above, as emerging evidence suggests that brain disorders are far more heterogeneous than the classification suggests.[4,8]
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