Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing ...Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of
, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.
Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We ...report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly.
Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated ...with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, “ribbon-like” heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.
NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the ...“NALCN channelosome”, consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic
NALCN
and
UNC80
variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo
NALCN
missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic
NALCN
variants, 1 individual with a heterozygous de novo
NALCN
missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic
UNC80
variants. We report for the first time a missense
NALCN
variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.
The integrity and dynamic properties of the microtubule cytoskeleton are indispensable for the development of the mammalian brain. Consequently, mutations in the genes that encode the structural ...component (the α/β-tubulin heterodimer) can give rise to severe, sporadic neurodevelopmental disorders. These are commonly referred to as the tubulinopathies. Here we report the addition of recessive quadrupedalism, also known as Uner Tan syndrome (UTS), to the growing list of diseases caused by tubulin variants. Analysis of a consanguineous UTS family identified a biallelic TUBB2B mutation, resulting in a p.R390Q amino acid substitution. In addition to the identifying quadrupedal locomotion, all three patients showed severe cerebellar hypoplasia. None, however, displayed the basal ganglia malformations typically associated with TUBB2B mutations. Functional analysis of the R390Q substitution revealed that it did not affect the ability of β-tubulin to fold or become assembled into the α/β-heterodimer, nor did it influence the incorporation of mutant-containing heterodimers into microtubule polymers. The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal conditions, but did result in increased sensitivity to microtubule-depolymerizing drugs, indicative of a mild impact of this mutation on microtubule function. The TUBB2B mutation described here represents an unusual recessive mode of inheritance for missense-mediated tubulinopathies and reinforces the sensitivity of the developing cerebellum to microtubule defects.
Objective
To identify causes of the autosomal‐recessive malformation, diencephalic‐mesencephalic junction dysplasia (DMJD) syndrome.
Methods
Eight families with DMJD were studied by whole‐exome or ...targeted sequencing, with detailed clinical and radiological characterization. Patient‐derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression.
Results
All patients showed biallelic mutations in the nonclustered
protocadherin‐12
(
PCDH12
) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of
PCDH12
in neural and endothelial cells. These cells showed lack of
PCDH12
expression and impaired neurite outgrowth.
Interpretation
DMJD patients have biallelic mutations in
PCDH12
and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with
PCDH12
‐related conditions. Ann Neurol 2018;84:638–647
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