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Truncating mutation in NFIA causes brain malformation and urinary tract defects

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Negishi Yutaka at Nagoya City University
Negishi Yutaka
Fuyuki Miya at Keio University
Fuyuki Miya
Ayako Hattori at Nagoya City University
Ayako Hattori
Kentaro Mizuno at Nagoya City University
Kentaro Mizuno
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Abstract and Figures

Chromosome 1p32-p31 deletion syndrome involving the Nuclear factor I/A (NFIA) gene is characterized by corpus callosum hypoplasia or defects and urinary tract defects. Herein we report on a case resembling the 1p32-p31 deletion syndrome carrying a de novo truncating mutation (c.1094delC; p.Pro365Hisfs*32) in the NFIA gene, confirming that haploinsufficiency of the NFIA gene is a major determinant of this syndrome. Chromosome 1p32-p31 deletion syndrome (OMIM #613735) involving the Nuclear factor I/A (NFIA) gene is characterized by corpus callosum hypoplasia or defects, hydrocephalus or ven-tricular enlargement and urinary tract defects. 1 Only six cases of this contiguous gene-deletion syndrome have been reported in the literature. 1–5 Additionally, Lu et al. 1 reported two patients showing a similar phenotype, but with balanced translocations breakpoints in the NFIA gene. 6 These authors also demonstrated ventricular enlargement, callosal agenesis and urinary tract defects in homozygous Nfia − / − mice and heterozygous Nfia +/ − mice.
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OPEN
DATA REPORT
Truncating mutation in NFIA causes brain malformation
and urinary tract defects
Yutaka Negishi
1,10
, Fuyuki Miya
2,10
, Ayako Hattori
1
, Kentaro Mizuno
3
, Ikumi Hori
1
, Naoki Ando
1
, Nobuhiko Okamoto
4
, Mitsuhiro Kato
5
,
Tatsuhiko Tsunoda
2
, Mami Yamasaki
6
, Yonehiro Kanemura
7,8
, Kenjiro Kosaki
9
and Shinji Saitoh
1
Chromosome 1p32-p31 deletion syndrome involving the Nuclear factor I/A (NFIA) gene is characterized by corpus callosum
hypoplasia or defects and urinary tract defects. Herein we report on a case resembling the 1p32-p31 deletion syndrome carrying a
de novo truncating mutation (c.1094delC; p.Pro365Hisfs*32) in the NFIA gene, confirming that haploinsufficiency of the NFIA gene is
a major determinant of this syndrome.
Human Genome Variation (2015) 2, 15007; doi:10.1038/hgv.2015.7; published online 26 February 2015
Chromosome 1p32-p31 deletion syndrome (OMIM #613735)
involving the Nuclear factor I/A (NFIA) gene is characterized by
corpus callosum hypoplasia or defects, hydrocephalus or ven-
tricular enlargement and urinary tract defects.
1
Only six cases of
this contiguous gene-deletion syndrome have been reported in
the literature.
1–5
Additionally, Lu et al.
1
reported two patients
showing a similar phenotype, but with balanced translocations
breakpoints in the NFIA gene.
6
These authors also demonstrated
ventricular enlargement, callosal agenesis and urinary tract defects
in homozygous Nfia
−/−
mice and heterozygous Nfia
+/ −
mice.
1
Recently, Rao et al.
7
reported a case exhibiting a similar phenotype
with an intragenic deletion in the NFIA gene, but no structural
chromosomal abnormalities detected by CGH microarray.
Although haploinsufficiency of the NFIA gene is considered the
main contributor to the phenotype of this chromosome 1p32-p31
deletion syndrome, the evidence is not conclusive because no
single nucleotide variant (SNV) in the NFIA gene has been
identified and chromosomal rearrangements including deletion or
translocation could have a position effect disturbing the proper
expression of the neighboring genes.
We herein report on a case of an individual showing
interhemispheric cysts, ventricular enlargement, callosal agenesis
and urinary tract defects, and carrying a heterozygous de novo
frameshift mutation in the NFIA gene. These findings provide
further strong evidence that haploinsufficiency of the NFIA gene is
a main contributor of 1p32-p31 deletion syndrome, and the NFIA
gene has a fundamental role in development of brain as well as
urinary tract.
This study was approved by the institutional review board of
Nagoya City University Graduate School of Medical Sciences.
The proband is a 5-year-old boy with no family history of the
relevant diseases. Callosal agenesis was suspected from the 28th
gestational week of the fetal period. The boy was born by
cesarean section on the 41st gestational week due to enlargement
of the head circumference and post-term pregnancy. His Apgar
score was 9 at 5 min post partum, his weight was 3180 g (+0.4 s.d.)
and his head circumference was 38.2 cm (+3.3 s.d.). No apparent
external malformations were observed. Head magnetic resonance
imaging (MRI) on the third day of life revealed interhemispheric
cysts, ventricular enlargement and callosal agenesis; however, he
was in good general condition. Regarding his developmental
milestones, he was able to hold his head up by 4 months and
started walking without support at 1 year and 3 months. He was
observed speaking meaningful words at 2 years and 1 month,
showing a slight delay in language, and his intelligence quotient
at 4 years measured by the Tanaka–Binet Intelligence Scale was
75. No epileptic seizures have been observed to date, although
electroencephalogram detected sharp waves in the frontal head
area at 11 months. A follow-up MRI at 4 years revealed
polymicrogyria in the right frontal lobe, while the size of the
interhemispheric cysts, longitudinal cerebral fissure and ventricu-
lar system remained unchanged (Figures 1a,b). Although no
abnormal signals were observed in the spinal cord in a spine MRI
carried out at 5 years, cystectasia and left hydronephrosis were
observed. A voiding cysturethrogram performed at 5 years
showed bilateral grade IV vesicoureteral reflux (Figure 1c). His
current head circumference is 56.1 cm (+3.8 s.d.) showing non-
progressive enlargement of head circumference. He showed only
a little dysmorphic facial features including mild macrocephaly,
high forehead, and thin upper lip (Figure 1d).
We performed a whole-exome sequencing on the proband and
his parents (Figure 2a). To do this, genomic DNA was extracted
from peripheral blood using the QIAamp DNA Blood Midi Kit
according to the manufacturer’s instructions (Qiagen, Tokyo,
Japan). Three micrograms of DNA was sheared into 150-200-bp
fragments using the Covaris DNA Shearing service (Covaris,
1
Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoy a, Japan;
2
Laboratory for Medical Science Mathematics, RIKEN
Center for Integrative Medical Sciences, Yokohama, Japan;
3
Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan;
4
Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan;
5
Department of Pediatrics, Yamagata University
Faculty of Medicine, Yamagata, Japan;
6
Department of Neurosurgery, Takatsuki General Hospital, Osaka, Japan;
7
Division of Regenerative Medicine, Institute for Clinical Research,
Osaka National Hospital, National Hospital Organization, Osaka, Japan;
8
Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan and
9
Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
Correspondence: S Saitoh (ss11@med.nagoya-cu.ac.jp)
10
These authors contributed equally to this work.
Received 1 September 2014; revised 26 November 2014; accepted 25 December 2014
Citation: Human Genome Variation (2015) 2, 15007; doi:10.1038/hgv.2015.7
© 2015 The Japan Society of Human Genetics All rights reserved 2054-345X/15
www.nature.com/hgv
Woburn, MA, USA). To capture the exonic DNA, we used the
SureSelect XT Human All Exon V5 capture library (Agilent
Technologies, Santa Clara, CA, USA). We then constructed a
sequence library using the SureSelect XT Target Enrichment
System for Illumina Paired-End Sequencing Library kit (Agilent
Technologies), and performed DNA sequencing of 100-bp paired-
end reads by using the Illumina HiSeq 2000 sequencer (Illumina,
San Diego, CA, USA). On average, we obtained 5.85 Gb of
sequence reads. The sequencing data was mapped to a reference
genome (GRCh37/hg19) using Burrows-Wheeler Alignment tool
(ver.0.6.1; http://www.bio-bwa.sourceforge.net/), and the average
read depth of targeted regions was 67.5. Variant calling was
performed using SAMtools (ver.0.1.16; http://www.samtools.
sourceforge.net/) and GATK (ver.1.6; http://www.broadinstitute.
org/gatk/) software. To identify the disease causative mutations,
we excluded known variants found in public databases
(dbSNP138, 1000 Genomes Project, and NHLBI ESP6500) and a
control in-house database (154 Japanese individuals of normal
and other diseases control), except for those also identified as
pathogenic mutations in the NCBI ClinVar (http://www.ncbi.nlm.
nih.gov/clinvar/) and HGMD databases (http://www.hgmd.org/).
We focused on non-synonymous SNVs, insertions and deletions
(indels), and splice-site variants (Figure 2b). This analysis revealed
a heterozygous frameshift mutation (c.1094delC; p.Pro365-
Hisfs*32) in the NFIA gene (NM_001134673.3), which is absent in
his parents, indicating that the mutation arose de novo (Figure 2c).
The mutation was confirmed by Sanger sequencing (Figure 2d).
This deletion led to an open reading frameshift that introduced an
early stop codon which truncated 114 aminoacids. Consequently,
a truncated NFIA protein is generated by this mutation.
The NFIA gene has four transcriptional variants in human.
Functional significance of each isoform has not been clarified.
Only isoform 2 lacks an alternative exon downstream of the
identified deletion site (Supplementary Figure a). The c.1094delC
mutation would create protein truncation in each isoform. To
examine the expression level of each transcript PCR with reverse
transcription reaction was performed by using RNA isolated from
normal human brain tissues (adult cortex, cerebellum, spinal cord
and fetal brain). NFIA isoform 2 transcript was less predominant
compared with isoforms 1, 3 and 4 (Supplementary Figure b).
Therefore, the c.1094delC mutation would induce more effects on
longer isoforms 1, 3 and 4 than on isoform 2, and the exon of
deletion site and/or next exon which are used in all wild-type
isoforms as translation regions would have an important role in
NFIA protein.
Three molecular mechanisms are known to cause the complex
central nervous system malformation syndrome associated with
the NFIA gene: (1) interstitial deletion of chromosome 1p32-p31
involving the NFIA gene; (2) translocations of chromosome
1p32-p31 involving the NFIA gene; and (3) intragenic deletion in
Figure 1. Head MRI, voiding cysturethrogram (VCUG) and craniofacial appearance of our patient. (a) Axial T2-weighted image showing
interhemispheric cysts, ventricular enlargement and polymicrogyria (arrow). (b) Mid-sagittal T1-weighted image showing callosal agenesis
(asterisk). (c) The VCUG showed bilateral grade IV vesicoureteral reflux. (d) Representative photograph of the patient showing a little
dysmorphic facial features including mild macrocephaly, high forehead, and thin upper lip. His parents gave informed consent for publication
of this image.
NFIA mutation causes brain malformation and VUR
Y Negishi et al
2
Human Genome Variation (2015) 15007 © 2015 The Japan Society of Human Genetics
the NFIA gene. Nine cases (6 deletions, 2 translocations and 1
intragenic deletion) of this syndrome have been reported to
date,
1–7
with corpus callosum hypoplasia or defects and hydro-
cephalus, ventricular enlargement and developmental delays
observed in all cases. Urinary tract defects, tethered spinal cord
and type 1 Chiari malformation were also observed in six, four and
three cases, respectively. Additionally, abnormal facies and marble
skin have been reported. The present case showed ventricular
enlargement, callosal agenesis, urinary tract defects, mildly
dysmorphic facial features and an intelligence quotient in the
borderline range. Thus, our case showed virtually the same
phenotype as 1p32-p31 deletion syndrome. Since the single
nucleotide deletion detected in our case is not likely to cause a
position effect affecting surrounding genes, it indicates that
haploinsufficiency of the NFIA gene is a major determinant of this
syndrome.
A truncating mutation in the NFIA gene was previously reported
in one patient with autistic spectrum disorder (c.112C4T;
p.R38*),
8
but detailed clinical information was not available.
Since urinary tract involvement is easily missed, it is conceivable
that this previous patient may have the same phenotype, and
comprehensive evaluation of the patient might uncover the
underlying defects.
The NFIA gene encodes a member of the nuclear factor I (NFI)
family of transcription factors.
9
NFI proteins control a range of key
processes in central nervous system development including axon
guidance and outgrowth, glial and neuronal cell differentiation,
and neuronal migration.
10
Additionally, these molecules regulate
midline glia formation in the cortex
11
and gliogenesis within the
spinal cord.
12
Thus, NFI functional defects could result in abnormal
brain formation, especially in midline structures, and spinal cord
defects leading to neurogenic urinary tract dysfunction and defects.
Interestingly, haploinsufficiency of the NFIB and NFIX genes, which
belong to the same NFI family, also cause callosal agenesis,
13–15
and
missense mutations in the NFIX gene cause Sotos-like syndrome.
14,16
Our case also demonstrated prominent macrocephaly, which is a
major feature of Sotos syndrome. Therefore, mutations in NFI family
genes may give rise to similar clinical presentations that encompass
callosal agenesis and macrocephaly.
In our case, identification of the mutation by whole-exome
sequencing led us to identify urinary tract defects in the
presymptomatic period, and untreated higher grades of
vesicoureteral reflux may have resulted in renal scar formation.
17
Therefore, whole-exome sequencing can be a powerful tool in
clinical practice for early diagnosis of congenital disorders.
HGV DATABASE
The relevant data from this Data Report are hosted at the
Human Genome Variation Database at http://dx.doi.org/10.6084/
m9.figshare.hgv.574.
ACKNOWLEDGEMENTS
This study was supported in part by a grant for Research on Applying Health
Technology from the Ministry of Health, Labour and Welfare of Japan to FM, NO, MK,
MY, YK, KK and SS. We thank KA Boroevich for English proofreading.
Figure 2. Genetic analysis of the pedigree. (a) Family tree of the pedigree. (b) Filtering the candidate mutations. Numbers show the patient
result. The top numbers indicate number of called variants by whole-exome sequencing. The second numbers indicate number of variants
after filter out known variants in databases, except for those which were also known pathogenic mutations. The third number indicates
number of variants after excluded synonymous change variants. The bottom numbers indicate number of variants consistent with the
phenotype in the pedigree (that is, total of the de novo, autosomal recessive, X-linked and compound heterozygous variants). Finally, only one
deletion variant was remained. (c) Identified frameshift mutation in the NFIA gene. (d) Sanger sequencing of the NFIA mutation. Patient had a
heterozygous c.1094delC mutation (arrow) not found in his parents.
NFIA mutation causes brain malformation and VUR
Y Negishi et al
3
© 2015 The Japan Society of Human Genetics Human Genome Variation (2015) 15007
COMPETING INTERESTS
The authors declare no conflict of interest.
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NFIA mutation causes brain malformation and VUR
Y Negishi et al
4
Human Genome Variation (2015) 15007 © 2015 The Japan Society of Human Genetics

Supplementary resources (4)

Supplementary Figure
Data
February 2015
Negishi Yutaka · Fuyuki Miya · Ayako Hattori · Kentaro Mizuno · Shinji Saitoh
hgv20157 SupplementaryFigure
Data
August 2015
Negishi Yutaka · Fuyuki Miya · Ayako Hattori · Kentaro Mizuno · Shinji Saitoh
hgv20157 SupplementaryFigure
Data
August 2015
Negishi Yutaka · Fuyuki Miya · Ayako Hattori · Kentaro Mizuno · Shinji Saitoh
hgv20157 SupplementaryFigure
Data
August 2015
Negishi Yutaka · Fuyuki Miya · Ayako Hattori · Kentaro Mizuno · Shinji Saitoh
... These results are reported in Table 1, along with the genetic alterations of the selected patients [17][18][19][20][21][22][23][24][25]. ...
... In Table 1 are listed our two cases along with the other 24 selected patients; their age ranges from 1-to 42-years-old; the prevalence of males and females is comparable (12 males versus 14 females); in four cases, the variants have been inherited, and twelve were de novo [17][18][19][20][21][22][23][24][25]. ...
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The NFIA (nuclear factor I/A) gene encodes for a transcription factor belonging to the nuclear factor I family and has key roles in various embryonic differentiation pathways. In humans, NFIA is the major contributor to the phenotypic traits of “Chromosome 1p32p31 deletion syndrome”. We report on two new cases with deletions involving NFIA without any other pathogenic protein-coding gene alterations. A cohort of 24 patients with NFIA haploinsufficiency as the sole anomaly was selected by reviewing the literature and public databases in order to analyze all clinical features reported and their relative frequencies. This process was useful because it provided an overall picture of the phenotypic outcome of NFIA haploinsufficiency and helped to define a cluster of phenotypic traits that can facilitate clinicians in identifying affected patients. NFIA haploinsufficiency can be suspected by a careful observation of the dysmorphisms (macrocephaly, craniofacial, and first-finger anomalies), and this potential diagnosis is strengthened by the presence of intellectual and developmental disabilities or other neurodevelopmental disorders. Further clues of NFIA haploinsufficiency can be provided by instrumental tests such as MRI and kidney urinary tract ultrasound and confirmed by genetic testing.
View
... Several balanced and unbalanced events with breakpoints disrupting NFIA have been reported previously 19 , suggesting that this gene may be prone to rearrangement. Similar to the previous cases with variants in NFIA (#MIM 613735), which causes brain malformations with or without urinary tract defect [19][20][21] , FIN66 had polymicrogyria (Suppl. Fig. 4), seizures, and long-lasting feeding problems. ...
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... [2] described five individuals presenting a new condition of central nervous system (CNS) malformations (abnormalities of the corpus callosum, hydrocephalus/ventriculomegaly, type I Chiari malformation) associated with urinary tract defects (mainly vesicoureteral reflux), besides developmental delay and seizures; two of them presented balanced translocations disrupting the NFIA gene and three had interstitial microdeletions involving the same gene. These authors suggested the role of NFIA as causative of this new disorder based on murine models [13] and later supported by further reports of additional patients presenting similar clinical pictures and intragenic deletions of several exons [4, 7,14] or loss-of-function mutations caused by missense, nonsense, and frameshift variant sequences [8,15]. ...
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b> Background: The chromosome 1p32p31 deletion syndrome is a contiguous gene disorder with a variable phenotype characterized by brain malformations with or without urinary tract defects, besides neurodevelopmental delay and dysmorphisms. An expanded phenotype was proposed based on additional findings, including one previous report of a patient presenting with moyamoya disease. Case Presentation: The authors report a patient presenting with early neurodevelopmental delay, hydrocephalus, renal malformation, and dysmorphisms. After presenting with a sudden choreic movement disorder, the neuroimaging investigation revealed an ischemic stroke, moyamoya disease, and bilateral incomplete hippocampal inversion. Chromosomal microarray analysis revealed a deletion of 13.2 Mb at 1p31.3p32.2, compatible with the contiguous gene syndrome caused by microdeletions of this region. Discussion/Conclusion: This is the second report of a patient who developed Moyamoya disease and the first to describe bilateral incomplete hippocampal inversion in this microdeletion syndrome.
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... NFIA has been linked to callosal hypoplasia, which likely reflects malformations of upper-layer excitatory neurons, and language delay, which was an enriched term for ExN L2-3 IT ( fig. S6D and 6E) (28). By analyzing the distribution of accessible chromatin peaks in the vicinity of NFIA across the two neuronal subclasses and developmental periods, we identified 8 active MEIS2 binding sites within 200kb upstream from the NFIA transcription start site (Fig. 3G). ...
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... Deletions of chromosome 1p32-p31 (MIM: 613735) as well as deletions or sequence variations of NFIA lead to a variable phenotype characterized by global developmental delay, ID, central nervous system malformations (loss of white matter, polymicrogyria and hypoplastic falx cerebri, partial inversion of the hippocampi), macrocephaly, and craniofacial dysmorphisms (Bayat et al., 2017;Campbell et al., 2002;Koehler et al., 2010;Labonne et al., 2016;Lu et al., 2007;Negishi et al., 2015;Nyboe et al., 2015;Rao et al., 2014;Shanske et al., 2004;Zinner & Batanian, 2003). Marshall-Smith syndrome is due to exon deletions, indels and splice site variants leading to frameshift downstream of Exon 5; the mutant NFIX protein has a preserved DNA binding and dimerization domain, and therefore likely acts in a dominant negative manner. ...
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Full-text available
  • Mar 2024
Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC is a component of a wide array of genetic syndromes as well as a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.) that can present across the age spectrum, highlighting the phenotypic heterogeneity of the disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both of which are prone to failure, and no effective pharmacologic treatments for HC have been developed. Thus, there is an urgent need to understand the genetic architecture and molecular pathogenesis of HC. Without this knowledge, the development of preventive, diagnostic, and therapeutic measures is impeded. However, the genetics of HC is extraordinarily complex, based on studies of varying size, scope, and rigor. This review serves to provide a comprehensive overview of genes, pathways, mechanisms, and global impact of genetics contributing to all etiologies of HC in humans.
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Significant phenotypic variability in a multigenerational family with an NFIA missense mutation: Case series and review of the literature
Article
Full-text available
  • Jan 2024
Key Clinical Message We report the first multigenerational family with NFIA‐related disorder from a missense variant. This case highlights the condition's phenotypic variability and the need for genetic testing when an initial diagnosis fails to explain all symptoms.
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NFIA haploinsufficiency: case series and literature review
Article
Full-text available
  • Oct 2023
Background NFIA -related disorder (OMIM #613735) is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment and non-specific dysmorphic features. To date, fewer than thirty patients affected by this disorder have been described. Methods Our study included three children with NFIA haploinsufficiency recruited from three medical genetics centers. Clinical presentations were recorded on a standardized case report form. Results All patients presented a variable degree of intellectual disability. None of the individuals in our cohort had urinary tract malformations. Three novel mutations, c.344G>A, c.261T>G, and c.887_888del are reported here. Conclusion NFIA haploinsufficiency can be suspected through careful observation of specific dysmorphisms, including macrocephaly and craniofacial abnormalities. Instrumental tests such as MRI and renal ultrasound provide further diagnostic clues, while genetic testing can confirm the diagnosis.
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Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria
Article
  • Jul 2023
Importance: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases. Objective: To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations. Design, setting, and participants: This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control. Main outcomes and measures: The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed. Results: In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families. Conclusions and relevance: This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.
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An intragenic deletion of the NFIA gene in a patient with a hypoplastic corpus callosum, craniofacial abnormalities and urinary tract defects
Article
Full-text available
  • Jan 2014
Chromosome 1p31 deletion (OMIM #613735) involving the NFIA gene (OMIM 600727) is characterised by variable defects in the formation of the corpus callosum, craniofacial abnormalities and urinary tract defects. A review of current literature suggests only seven cases have been reported, none of which had an isolated NFIA gene defect. We submit the clinical and molecular features of an 8-year-old female patient with a microdeletion of chromosome 1p31.3 who has developmental delay, metopic synostosis and macroscopic haemoglobinuria. She was investigated with karyotyping, subtelomeric FISH and microarray CGH. Array CGH identified a single 120kb microdeletion of 1p31.3 involving exons 4-9 of the NFIA gene. Her brain MRI showed hypoplasia of the corpus callosum especially in the posterior areas. Karyotype was normal, ruling out structural chromosomal abnormalities. In this study, we confirmed that a microdeletion in the chromosome region 1p31.3 involving the NFIA gene is associated with hypoplasia of the corpus callosum, developmental delay, metopic synostosis and urinary tract abnormalities. Furthermore, we propose a mechanism by which disruptions in the NFIA gene causes craniofacial abnormalities. This report presents the first case of an intragenic deletion within the NFIA gene that is still consistent with classic clinical phenotypes present in previously reported cases of chromosome 1p31.3 related deletion. This finding will help clarify the role of the NFIA gene in the normal formation of parts of the CNS, the craniofacial complex and the urinary tract.
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Both Rare and De Novo Copy Number Variants Are Prevalent in Agenesis of the Corpus Callosum but Not in Cerebellar Hypoplasia or Polymicrogyria
Article
Full-text available
Agenesis of the corpus callosum (ACC), cerebellar hypoplasia (CBLH), and polymicrogyria (PMG) are severe congenital brain malformations with largely undiscovered causes. We conducted a large-scale chromosomal copy number variation (CNV) discovery effort in 255 ACC, 220 CBLH, and 147 PMG patients, and 2,349 controls. Compared to controls, significantly more ACC, but unexpectedly not CBLH or PMG patients, had rare genic CNVs over one megabase (p = 1.48×10(-3); odds ratio [OR] = 3.19; 95% confidence interval [CI] = 1.89-5.39). Rare genic CNVs were those that impacted at least one gene in less than 1% of the combined population of patients and controls. Compared to controls, significantly more ACC but not CBLH or PMG patients had rare CNVs impacting over 20 genes (p = 0.01; OR = 2.95; 95% CI = 1.69-5.18). Independent qPCR confirmation showed that 9.4% of ACC patients had de novo CNVs. These, in comparison to inherited CNVs, preferentially overlapped de novo CNVs previously observed in patients with autism spectrum disorders (p = 3.06×10(-4); OR = 7.55; 95% CI = 2.40-23.72). Interestingly, numerous reports have shown a reduced corpus callosum area in autistic patients, and diminished social and executive function in many ACC patients. We also confirmed and refined previously known CNVs, including significantly narrowing the 8p23.1-p11.1 duplication present in 2% of our current ACC cohort. We found six novel CNVs, each in a single patient, that are likely deleterious: deletions of 1p31.3-p31.1, 1q31.2-q31.3, 5q23.1, and 15q11.2-q13.1; and duplications of 2q11.2-q13 and 11p14.3-p14.2. One ACC patient with microcephaly had a paternally inherited deletion of 16p13.11 that included NDE1. Exome sequencing identified a recessive maternally inherited nonsense mutation in the non-deleted allele of NDE1, revealing the complexity of ACC genetics. This is the first systematic study of CNVs in congenital brain malformations, and shows a much higher prevalence of large gene-rich CNVs in ACC than in CBLH and PMG.
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Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features
Article
Full-text available
  • Feb 2012
  • J HUM GENET
Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T>C (p.Leu60Pro) mutation occurred de novo and the c.362G>C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.
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Chromosome 1p32-p31 deletion syndrome: Prenatal diagnosis by array comparative genomic hybridization using uncultured amniocytes and association with NFIA haploinsufficiency, ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction
Article
Full-text available
  • Sep 2011
To present prenatal diagnosis of chromosome 1p32-p31 deletion syndrome with NFIA haploinsufficiency, ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction and to review the literature. A 26-year-old, primigravid woman was referred for amniocentesis at 30 weeks of gestation because of hydrocephalus and short limbs. Prenatal ultrasound showed macrocephaly, prominent forehead, ventriculomegaly, corpus callosum hypogenesis, micrognathia, and ambiguous external genitalia. Amniocentesis was performed, and array comparative genomic hybridization using uncultured amniocytes revealed a 22.2-Mb deletion of 1p32.3-p31.1 [arr cgh 1p32.3p31.1 (55,500,291 bp-77,711,982 bp)×1] encompassing the genes of NFIA, GPR177, and 89 additional genes. Cytogenetic analysis revealed a karyotype of 46,XX,del(1)(p31.1p32.3)dn. At 33 weeks of gestation, a dead fetus was delivered with a body weight of 1536g (<5(th) centile); relative macrocephaly; a broad face; prominent forehead; hypertelorism; anteverted nostrils; micrognathia; low-set ears; and abnormal female external genitalia with labial fusion, labial hypertrophy, absence of vaginal opening, and clitoral hypertrophy. Polymorphic DNA marker analysis determined a paternal origin of the deletion. Prenatal diagnosis of ventriculomegaly with an abnormal corpus callosum should alert subtle chromosome aberrations and prompt molecular cytogenetic investigation if necessary. Fetuses with chromosome 1p32-p31 deletion syndrome and haploinsufficiency of the NFIA gene may present ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction in the third trimester.
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A novel 1p31.3p32.2 deletion involving the NFIA gene detected by array CGH in a patient with macrocephaly and hypoplasia of the corpus callosum
Article
Full-text available
  • Sep 2009
  • Eur J Pediatr
Interstitial deletions or apparently balanced translocations involving bands 1p31 and 1p32 in the short arm of chromosome 1 are rarely described chromosomal imbalances. To our knowledge, there have been six cases documented to date. Five of these cases, where the NFIA gene is involved, show complex central nervous system malformations and in some cases urinary tract defects. We report another case of a microdeletion with involvement of the NFIA gene in the short arm of chromosome 1 (del(1)(p31.3p32.2)) with, amongst other features, hypoplasia of the corpus callosum, ventriculomegaly, and dysmorphic features. A microdeletion 1p31.3p32.2 which includes the NFIA gene is associated with hypoplasia of the corpus callosum, ventriculomegaly, and dysmorphic features.
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Nuclear Factor One Transcription Factors in CNS Development
Article
Full-text available
  • Feb 2009
Transcription factors are key regulators of central nervous system (CNS) development and brain function. Research in this area has now uncovered a new key player-the nuclear factor one (NFI) gene family. It has been almost a decade since the phenotype of the null mouse mutant for the nuclear factor one A transcription factor was reported. Nfia null mice display a striking brain phenotype including agenesis of the corpus callosum and malformation of midline glial populations needed to guide axons of the corpus callosum across the midline of the developing brain. Besides NFIA, there are three other NFI family members in vertebrates: NFIB, NFIC, and NFIX. Since generation of the Nfia knockout (KO) mice, KO mice for all other family members have been generated, and defects in one or more organ systems have been identified for all four NFI family members (collectively referred to as NFI here). Like the Nfia KO mice, the Nfib and Nfix KO mice also display a brain phenotype, with the Nfib KO forebrain phenotype being remarkably similar to that of Nfia. Over the past few years, studies have highlighted NFI as a key payer in a variety of CNS processes including axonal outgrowth and guidance and glial and neuronal cell differentiation. Here, we discuss the importance and role of NFI in these processes in the context of several CNS systems including the neocortex, hippocampus, cerebellum, and spinal cord at both cellular and molecular levels.
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De Novo Gene Disruptions in Children on the Autistic Spectrum
Article
  • Apr 2012
Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.
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Distinct Effects of Allelic NFIX Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome
Article
  • Aug 2010
  • AM J HUM GENET
By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (NFIX) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, Nfix-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider NFIX as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice NFIX mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that NFIX is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic NFIX mutations trigger distinct phenotypes, depending specifically on their impact on NMD.
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Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children
Article
  • Sep 2010
  • J UROLOGY
The American Urological Association established the Vesicoureteral Reflux Guideline Update Committee in July 2005 to update the management of primary vesicoureteral reflux in children guideline. The Panel defined the task into 5 topics pertaining to specific vesicoureteral reflux management issues, which correspond to the management of 3 distinct index patients and the screening of 2 distinct index patients. This report summarizes the existing evidence pertaining to children with diagnosed reflux including those young or older than 1 year without evidence of bladder and bowel dysfunction and those older than 1 year with evidence of bladder and bowel dysfunction. From this evidence clinical practice guidelines were developed to manage the clinical scenarios insofar as the data permit. The Panel searched the MEDLINE(R) database from 1994 to 2008 for all relevant articles dealing with the 5 chosen guideline topics. The database was reviewed and each abstract segregated into a specific topic area. Exclusions were case reports, basic science, secondary reflux, review articles and not relevant. The extracted article to be accepted should have assessed a cohort of children with vesicoureteral reflux and a defined care program that permitted identification of cohort specific clinical outcomes. The reporting of meta-analysis of observational studies elaborated by the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) group was followed. The extracted data were analyzed and formulated into evidence-based recommendations. A total of 2,028 articles were reviewed and data were extracted from 131 articles. Data from 17,972 patients were included in this analysis. This systematic meta-analysis identified increasing frequency of urinary tract infection, increasing grade of vesicoureteral reflux and presence of bladder and bowel dysfunction as unique risk factors for renal cortical scarring. The efficacy of continuous antibiotic prophylaxis could not be established with current data. However, its purported lack of efficacy, as reported in selected prospective clinical trials, also is unproven owing to significant limitations in these studies. Reflux resolution and endoscopic surgical success rates are dependent upon bladder and bowel dysfunction. The Panel then structured guidelines for clinical vesicoureteral reflux management based on the goals of minimizing the risk of acute infection and renal injury, while minimizing the morbidity of testing and management. These guidelines are specific to children based on age as well as the presence of bladder and bowel dysfunction. Recommendations for long-term followup based on risk level are also included. Using a structured, formal meta-analytic technique with rigorous data selection, conditioning and quality assessment, we attempted to structure clinically relevant guidelines for managing vesicoureteral reflux in children. The lack of robust prospective randomized controlled trials limits the strength of these guidelines but they can serve to provide a framework for practice and set boundaries for safe and effective practice. As new data emerge, these guidelines will necessarily evolve.
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