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1.
Am J Hum Genet ; 103(5): 752-768, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

2.
Nat Genet ; 49(1): 36-45, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27841880

RESUMO

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.


Assuntos
Aberrações Cromossômicas , Anormalidades Congênitas/genética , Rearranjo Gênico , Marcadores Genéticos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Feminino , Humanos , Masculino
3.
Eur J Hum Genet ; 22(4): 464-70, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23963300

RESUMO

Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Cromossomos Humanos Par 4/genética , Histona-Lisina N-Metiltransferase/genética , Proteínas de Membrana/genética , Proteínas Repressoras/genética , Síndrome de Wolf-Hirschhorn/genética , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Fenótipo , Deleção de Sequência , Síndrome de Wolf-Hirschhorn/diagnóstico
4.
Am J Hum Genet ; 92(1): 137-43, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23273567

RESUMO

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases.


Assuntos
Mutação , Osteocondrodisplasias/genética , Monoéster Fosfórico Hidrolases/genética , Criança , Pré-Escolar , Feminino , Genoma Humano , Humanos , Lactente , Recém-Nascido , Masculino , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases
5.
Am J Hum Genet ; 92(1): 150-6, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23261301

RESUMO

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ~50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ~70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.


Assuntos
Artrogripose/genética , Metaloendopeptidases/genética , Consanguinidade , Feminino , Ligação Genética , Humanos , Masculino , Mutação , Análise de Sequência de DNA
6.
J Pediatr ; 146(2): 258-62, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15689920

RESUMO

OBJECTIVES: We compare positioning with orthotic therapy in 298 consecutive infants referred for correction of head asymmetry. STUDY DESIGN: We evaluated 176 infants treated with repositioning, 159 treated with helmets, and 37 treated with initial repositioning followed by helmet therapy when treatment failed. We compared reductions in diagonal difference (RDD) between repositioning and cranial orthotic therapy. Helmets were routinely used for infants older than 6 months with DD >1 cm. RESULTS: For infants treated with repositioning at a mean age of 4.8 months, the mean RDD was 0.55 cm (from an initial mean DD of 1.05 cm). For infants treated with cranial orthotics at a mean age of 6.6 months, the mean RDD was 0.71 cm (from an initial mean DD of 1.13 cm). CONCLUSIONS: Infants treated with orthotics were older and required a longer length of treatment (4.2 vs 3.5 months). Infants treated with orthosis had a mean final DD closer to the DD in unaffected infants (0.3 +/- 0.1 cm), orthotic therapy was more effective than repositioning (61% decrease versus 52% decrease in DD), and early orthosis was significantly more effective than later orthosis (65% decrease versus 51% decrease in DD).


Assuntos
Plagiocefalia não Sinostótica/terapia , Decúbito Dorsal/fisiologia , Fatores Etários , Oftalmopatias/etiologia , Oftalmopatias/terapia , Feminino , Dispositivos de Proteção da Cabeça , Humanos , Lactente , Estudos Longitudinais , Masculino , Plagiocefalia não Sinostótica/complicações , Plagiocefalia não Sinostótica/fisiopatologia , Crânio/anormalidades , Resultado do Tratamento
7.
Am J Med Genet A ; 120A(3): 400-5, 2003 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-12838563

RESUMO

In 1983, Johnson et al. described 16 related individuals with alopecia, anosmia or hyposmia, conductive hearing loss, microtia and/or atresia of the external auditory canal, and hypogonadotrophic hypogonadism inherited in an autosomal dominant pattern. Other less constant manifestations included facial asymmetry, mental retardation, congenital heart defect, cleft palate, and choanal stenosis. An isolated case was reported later (Johnston et al. [1987: Am J Med Genet 26: 925-927]) and thereafter an affected mother and son (Hennekam and Holtus [1993: Am J Med Genet 47: 714-716]). We describe an additional unrelated female patient with features resembling those of the previously reported cases. She presented with intrauterine growth deficiency, microcephaly, alopecia, bilateral microtia with canal atresia, conductive hearing loss, partial left facial palsy, posterior cleft palate, left choanal stenosis, tetralogy of Fallot, developmental delay, and right thumb polydactyly. Because the phenotypic abnormalities in this syndrome affect the brain, facial structures, ectoderm and its derivatives, outflow tract of the heart, and Rathke's pouch derivatives, this has suggested to previous authors etiologic involvement of the ectoderm and neuroectoderm of the first and second branchial arches, Rathke's pouch, and the diencephalon. Microtia with conductive hearing loss differentiates the condition from other ectodermal dysplasias. In the initial report, females appeared somewhat less affected than males, and there was male-to-male transmission. The mother of our patient manifests subtle features, which suggest she may be a mildly affected female. Additionally, there is a family history of early-onset alopecia in the maternal grandfather's relatives.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Perda Auditiva Condutiva/fisiopatologia , Síndromes Neurocutâneas/fisiopatologia , Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Perda Auditiva Condutiva/genética , Humanos , Lactente , Recém-Nascido , Síndromes Neurocutâneas/genética
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