Biomedical subjects

William B Dobyns

Publications and source records attributed to William B Dobyns.

At least 19 recordsLinked to original sources

PubMed2025

Patterns of X-linked inheritance: A new approach for the genome era.

PURPOSE: The concepts of X-linked (XL) dominant and recessive inheritance originated long before dosage compensation for X chromosome genes was understood, but now have no scientific basis. However, misunderstanding of the underlying biology persists, prompting our reassessment of XL inheritance. METHODS: We reviewed data on penetrance, expressivity, and X chromosome inactivation (XCI) for 55 XL genes and 57 XL disorders, and examined variations in inheritance based on disease severity, XCI status, cell selection, and other factors. RESULTS: Our analysis demonstrated widely varying penetrance among heterozygous females that was related to severity of the phenotype particularly in males, the degree of cell selection shown by XCI patterns, cell autonomous or non-cell autonomous function of the gene product, and rare cellular interference. CONCLUSION: The conventional classification of XL inheritance into dominant and recessive subtypes is biologically flawed and should be retired. A more nuanced framework for understanding XL disorders is needed that accounts for the underlying biological complexity, and we propose 4 new groups of XL disorders with different patterns that should improve genetic diagnosis and counseling in families with XL disorders.

Humans↗

PubMed2007

Truncation of NHEJ1 in a patient with polymicrogyria.

Polymicrogyria (PMG) is a common malformation of the human cerebral cortex for which both acquired and genetic causes are known. Although genetic heterogeneity is documented, only one gene is currently known to cause isolated PMG. To clone new genes involved in this type of cerebral malformation, we studied a fetus presenting a defect of cortical organization consisting of a polymicrogyric cortex and neuronal heterotopia within the white matter. Karyotype analysis revealed that the fetus was carrier of a balanced, de novo, chromosomal translocation t(2;7)(q35;p22). Cloning and sequencing of the two translocation breakpoints reveals that the chromosomal rearrangement disrupts the coding region of a single gene, called NHEJ1, Cernunnos, or XLF, in 2q35. The NHEJ1 gene was recently identified as being responsible for autosomal recessive immunodeficiency with microcephaly. Using quantitative PCR experiments, we show that a truncated transcript is expressed in the polymicrogyric patient cells, suggesting a potential dominant negative effect possibly leading to a different phenotype. We performed in situ hybridization on human embryos and showed that the NHEJ1 transcript is preferentially expressed in the telencephalic ventricular and subventricular zones, consistent with the phenotype of the affected individual. In the human adult central nervous system (CNS), NHEJ1 is mainly expressed in the cerebral cortex and in the cerebellum. The association of PMG with the disruption of its transcript suggests that, in addition to its recently uncovered function in the immune system, the NHEJ1 protein may also play a role during development of the human cerebral cortex.

Animals↗

PubMed2006

Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation.

Several brain malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the cortical malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain malformation associated with DEL22q11.

Cerebellum↗

PubMed2006

Carriers and patients with muscle-eye-brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts.

We report a new fibroblast and lymphoblast based protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 enzymatic assay, which allows rapid and accurate diagnosis of carriers and patients with muscle-eye-brain type of congenital muscular dystrophy. Seven patients with genetically confirmed muscle-eye-brain disease were assayed for protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 enzyme activity. In three patients and their heterozygous parents, the assays were done on EBV-transformed lymphoblasts, in another three patients they were done on cultured fibroblasts and in the last patient on both fibroblasts and lymphoblasts. Cultured fibroblasts and lymphoblasts from the muscle-eye-brain patients showed a highly significant decrease in protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity relative to controls. The residual protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 level in fibroblasts (average 0.11 nmoles/h per mg) was about 13% of normal controls. The ratio of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity to the activity of a glycosyltransferase control (N-acetylglucosaminyltransferase 1; GnT1) in fibroblasts was on average 0.006 in muscle-eye-brain patients and 0.045 in controls. The average residual protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 level in lymphoblasts was 15% of normal controls. The average ratio of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1/GnT1 activity was 0.007 in muscle-eye-brain patients, 0.026 in heterozygous carriers and 0.046 in normal controls. Assay of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity in fibroblasts and lymphoblasts from muscle-eye-brain carriers and patients provides a rapid and relatively simple diagnostic test for this disease and could be used as a screening test in carriers and patients with complex congenital muscular dystrophy.

Cells, Cultured↗

PubMed2006

Cerebellar ataxia with progressive improvement.

BACKGROUND: Nonprogressive cerebellar ataxias are characterized by a persistent, nonprogressive ataxia associated with cognitive impairment. Cerebellar hypoplasia on imaging is variable but is not predictive of the degree of ataxia or cognitive impairment. OBJECTIVE: To describe a family with a nonprogressive cerebellar ataxia associated with cognitive and motor impairments that improve with age. DESIGN: Genetic study in a family with nonprogressive cerebellar ataxia. Clinical and imaging features are also described. SETTING: Community hospital. PATIENTS: Both parents and 3 children from an affected family. MAIN OUTCOME MEASURES: Clinical features, magnetic resonance imaging findings, and genetic findings. RESULTS: A genome-wide single nucleotide polymorphism screen did not show clear linkage to known spinocerebellar ataxia loci, in particular spinocerebellar ataxia type 15. Repeat spinocerebellar ataxia loci expansions were excluded. Magnetic resonance images of all affected individuals demonstrated cerebellar vermian abnormalities. CONCLUSIONS: These findings suggest that nonprogressive cerebellar ataxia is genetically heterogeneous and, when associated with gradual improvement in cognition and motor skills, likely represents a separate, distinct clinical entity.

Adult↗

PubMed2006

AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.

OBJECTIVE: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. METHODS: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. RESULTS: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. INTERPRETATION: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Flores hominid: new species or microcephalic dwarf?

The proposed new hominid "Homo floresiensis" is based on specimens from cave deposits on the Indonesian island Flores. The primary evidence, dated at approximately 18,000 y, is a skull and partial skeleton of a very small but dentally adult individual (LB1). Incomplete specimens are attributed to eight additional individuals. Stone tools at the site are also attributed to H. floresiensis. The discoverers interpreted H. floresiensis as an insular dwarf derived from Homo erectus, but others see LB1 as a small-bodied microcephalic Homo sapiens. Study of virtual endocasts, including LB1 and a European microcephalic, purportedly excluded microcephaly, but reconsideration reveals several problems. The cranial capacity of LB1 ( approximately 400 cc) is smaller than in any other known hominid < 3.5 Ma and is far too small to derive from Homo erectus by normal dwarfing. By contrast, some associated tools were generated with a prepared-core technique previously unknown for H. erectus, including bladelets otherwise associated exclusively with H. sapiens. The single European microcephalic skull used in comparing virtual endocasts was particularly unsuitable. The specimen was a cast, not the original skull (traced to Stuttgart), from a 10-year-old child with massive pathology. Moreover, the calotte does not fit well with the rest of the cast, probably being a later addition of unknown history. Consideration of various forms of human microcephaly and of two adult specimens indicates that LB1 could well be a microcephalic Homo sapiens. This is the most likely explanation for the incongruous association of a small-brained recent hominid with advanced stone tools.

Animals↗

PubMed2006

The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked.

UNLABELLED: Our modern concepts of genetic inheritance originated nearly a century ago. Early concepts of dominant and recessive inheritance were developed in insects and were subsequently applied to sex-linked inheritance in mammals. Years of clinical experience, however, suggest that the modern-day rules for X-linked dominant and recessive diseases do not explain why so many female carriers of X-linked 'recessive' disorders have an abnormal phenotype. In a review of 32 X-linked diseases we revealed an unexpectedly high degree of intermediate disease penetrance in females that cannot be explained by existing concepts. We recommend that the terms 'dominant' and recessive' be abandoned and that these disorders be referred to as X-linked. In this review we will present modified rules for X-linked inheritance and propose hypotheses related to the potential mechanisms that may explain differences in disease expression in females. CONCLUSION: Past assumptions regarding factors that may affect phenotype in heterozygous females do not capture the extraordinarily variable expressivity of X-linked disorders in females and need to be revisited.

Animals↗

PubMed2005

Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder of infancy characterized by hydrocephalus, agyria, retinal dysplasia, congenital muscular dystrophy, and over migration of neurons through a disrupted pial surface resulting in leptomeningeal heterotopia. Although previous work identified mutations in the o-mannosyl transferase, POMT1, in 6 out of 30 WWS families [Beltran-Valero de Bernabe et al., 2002], the incidence of POMT1 mutations in WWS is not known. We sequenced the entire coding region of POMT1 in 30 consecutive, unselected patients with classic WWS. Two novel heterozygous mutations were found in two patients from non-consanguineous parents, whereas 28 other patients failed to show any POMT1 mutations. One patient was found to be heterozygous for a transition, g.1233T > A, which predicts p.Y352X. A second patient was found also to be heterozygous for a transition g.1790C > G, which predicts p.S537R. As an additional determination of the frequency of the POMT1 mutations in WWS, we tested for linkage of WWS to POMT1 in six consanguineous families. All six demonstrated heterozygosity and negative LOD scores at the POMT1 locus. From these data we show that POMT1 is an uncommon cause of WWS, the incidence of coding region mutations in this population of WWS being less than 7%. We conclude that while the incidence of POMT1 mutations in WWS can be as high as 20% as reported by Beltran-Valero de Bernabe et al. [2002] and it can be as low as approximately 7%, as reported here.

Abnormalities, Multiple↗

PubMed2005

Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes.

Human cerebral cortical polymicrogyria is a heterogeneous disorder, with only one known gene (GPR56) associated with an apparently distinctive phenotype, termed bilateral frontoparietal polymicrogyria (BFPP). To define the range of abnormalities that could be caused by human GPR56 mutations and to establish diagnostic criteria for BFPP, we analyzed the GPR56 gene in a cohort of 29 patients with typical BFPP. We identified homozygous GPR56 mutations in all 29 patients with typical BFPP. The total of 11 GPR56 mutations found represented a variety of distinct founder mutations in various populations throughout the world. In addition, we analyzed five patients with BFPP who did not show GPR56 mutation and found that they define a clinically, radiographically, and genetically distinct syndrome that we termed BFPP2. Finally, we studied seven patients with a variety of other polymicrogyria syndromes including bilateral frontal polymicrogyria, bilateral perisylvian polymicrogyria, and bilateral generalized polymicrogyria. No GPR56 mutation was found in these patients. This study provides a molecular confirmation of the BFPP phenotype and provides the wherewithal for diagnostic screening.

Adolescent↗

PubMed2005

Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome.

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.

Catalytic Domain↗

PubMed2005

Genetic links between brain development and brain evolution.

The most defining biological attribute of Homo sapiens is its enormous brain size and accompanying cognitive prowess. How this was achieved by means of genetic changes over the course of human evolution has fascinated biologists and the general public alike. Recent studies have shown that genes controlling brain development - notably those implicated in microcephaly (a congenital defect that is characterized by severely reduced brain size) - are favoured targets of natural selection during human evolution. We propose that genes that regulate brain size during development, such as microcephaly genes, are chief contributors in driving the evolutionary enlargement of the human brain. Based on the synthesis of recent studies, we propose a general methodological template for the genetic analysis of human evolution.

Animals↗

PubMed2005

Periventricular nodular heterotopia with overlying polymicrogyria.

Polymicrogyria (PMG) and periventricular nodular heterotopia (PNH) are two developmental brain malformations that have been described independently in multiple syndromes. Clinically, they present with epilepsy and developmental handicaps in both children and adults. Here we describe their occurrence together as the two major findings in a group of at least three cortical malformation syndromes. We identified 30 patients as having both PNH and PMG on brain imaging, reviewed clinical data and brain imaging studies (or neuropathology summary) for all, and performed mutation analysis of FLNA in nine patients. The group was divided into three subtypes based on brain imaging findings. The frontal-perisylvian PNH-PMG subtype included eight patients (seven males and one female) between 2 days and 10 years of age. It was characterized by PNH lining the lateral body and frontal horns of the lateral ventricles and by PMG most severe in the posterior frontal and perisylvian areas, occasionally with extension to the parietal lobes beyond the immediate perisylvian cortex. The posterior PNH-PMG subtype consisted of 20 patients (15 male and 5 female) between 5 days and 40 years of age. It was characterized by PNH in the trigones, temporal and posterior horns of the lateral ventricles, and PMG most severe in the temporo-parieto-occipital regions. The third type was found in 2 females aged 7 months and 2 years, and was characterized by severe congenital microcephaly and more diffuse cortical abnormality. The PNH-PMG subtypes described here have distinct imaging and clinical phenotypes that suggest multiple genetic aetiologies involving defects in multiple genes, and a shared pathophysiological mechanism for PNH and PMG. The frontal-perisylvian and posterior subtypes both had skewing of the sex ratio towards males, which suggests the possibility of X-linked inheritance. Delineation of these syndromes will also aid in providing more accurate diagnosis and prognostic information for patients with these malformations.

Adolescent↗

PubMed2005

Genotypically defined lissencephalies show distinct pathologies.

Lissencephaly is traditionally divided into 2 distinct pathologic forms: classic (type I) and cobblestone (type II). To date, mutations in 4 genes, LIS1, DCX, RELN, and ARX, have been associated with distinct type I lissencephaly syndromes. Each of these genes has been shown to play a role in normal cell migration, consistent with the presumed pathogenesis of type I lissencephaly. Based on these data, we hypothesized that all forms of radiographically defined type I lissencephaly independent of genotype would be pathologically similar. To test this hypothesis, we examined brains from 16 patients, including 15 lissencephalic patients and one patient with subcortical band heterotopia. Of these 16 patients, 6 had LIS1 deletions, 2 had DCX mutations, and 2 had ARX mutations. In addition, 6 patients had no defined genetic defect, although the patient with subcortical band heterotopia exhibited the same pattern of malformation expected with an XLIS mutation. In all cases, the cortex was thickened; however, the topographic distribution of the cortical pathology varied, ranging from frontal- to occipital-biased pathology to diffuse involvement of the neocortex. Although brains with LIS1 deletions exhibited the classic 4-layer lissencephalic architecture, patients with DCX and ARX mutations each had unique cytoarchitectural findings distinct from LIS1. Furthermore, 2 of the 5 patients with no known genetic defect showed a fourth type of histopathology characterized by a 2-layered cortex. Interestingly, the 2 brains with the fourth type of lissencephaly showed profound brainstem and cerebellar abnormalities. In summary, we identified at least 4 distinct histopathologic subtypes of lissencephaly that stratify with the underlying genetic defect. Based on these data, a new classification for lissencephaly is proposed that incorporates both pathologic and genetic findings.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2005

X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy".

X-linked lissencephaly with abnormal genitalia is the first human disorder in which deficient tangential migration in the brain has been demonstrated. Male patients with X-linked lissencephaly with abnormal genitalia show intractable seizures, especially clonic convulsions or myoclonus from the first day of life, but neither infantile spasms nor hypsarrhythmia on electroencephalograms so far. Brain magnetic resonance imaging shows anterior pachygyria and posterior agyria with a mildly thick cortex, agenesis of the corpus callosum, and dysplastic basal ganglia. ARX, a paired-class homeobox gene with four polyalanine sequences, is a responsible gene for X-linked lissencephaly with abnormal genitalia. The brain of Arx knockout mice shows aberrant tangential migration and differentiation of gamma-aminobutyric acid (GABA)ergic interneurons. In human X-linked lissencephaly with abnormal genitalia, a neuropathologic study has suggested a loss of interneurons. Meanwhile, polyalanine expansion of ARX causes symptomatic or nonsymptomatic West's syndrome and nonsyndromic mental retardation. The striking epileptogenicity of X-linked lissencephaly with abnormal genitalia and West's syndrome associated with ARX mutations i s considered to be caused by a disorder of interneurons involving a tangentialmigration disorder. We propose "interneuronopathy" as a term for this.

Cell Movement↗

PubMed2004

Inheritance of most X-linked traits is not dominant or recessive, just X-linked.

The existence of X-linked disorders in humans has been recognized for many centuries, based on lessons in religious texts and observations of specific human families (e.g., color blindness or Daltonism). Our modern concepts of Mendelian (including X-linked) inheritance originated just after the turn of the last century. Early concepts of dominance and recessiveness were first used in conjunction with autosomal traits, and then applied to "sex"-linked traits to distinguish X-linked recessive and X-linked dominant inheritance. The former was defined as vertical transmission in which carrier women pass the disorder to affected sons, while the latter was defined as vertical transmission in which daughters of affected males are always affected, transmitting the disorder to offspring of both sexes. However, many X-linked disorders such as adrenoleukodystrophy, fragile X syndrome, and ornithine transcarbamylase deficiency do not fit these rules. We reviewed the literature on 32 X-linked disorders and recorded information on penetrance and expressivity in both sexes. As expected, penetrance and an index of severity of the phenotype (defined in our Methods) were both high in males, while the severity index was low in females. Contrary to standard presentations of X-linked inheritance, penetrance was highly variable in females. Our analysis classified penetrance as high in 28% of the disorders studied, intermediate in 31%, and low in 40%. The high proportion of X-linked disorders with intermediate penetrance is difficult to reconcile with standard definitions of X-linked recessive and dominant inheritance. They do not capture the extraordinarily variable expressivity of X-linked disorders or take into account the multiple mechanisms that can result in disease expression in females, which include cell autonomous expression, skewed X-inactivation, clonal expansion, and somatic mosaicism. We recommend that use of the terms X-linked recessive and dominant be discontinued, and that all such disorders be simply described as following "X-linked" inheritance.

Chromosomes, Human, X↗

PubMed2004

Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation.

Dandy-Walker malformation (DWM; OMIM #220200) is a common but poorly understood congenital cerebellar malformation in humans. Through physical mapping of 3q2 interstitial deletions in several individuals with DWM, we defined the first critical region associated with DWM, encompassing two adjacent Zinc finger in cerebellum genes, ZIC1 and ZIC4. Mice with a heterozygous deletion of these two linked genes have a phenotype that closely resembles DWM, providing a mouse model for this malformation.

Animals↗

PubMed2004

MICRO syndrome: an entity distinct from COFS syndrome.

Children born with the findings of microcephaly, cataracts and microcornea can result not only from a prenatal viral infection, but also from an autosomal recessive Mendelian disorders. We present three pairs of affected siblings with MICRO syndrome, who were born with congenital microcephaly, microcornea, and cataracts. MICRO syndrome is an autosomal recessive syndrome consisting of congenital microcephaly, cortical dysplasia, microcornea, cataracts, optic atrophy, severe mental retardation, hypotonic diplegia, and hypogenitalism. At birth, MICRO syndrome resembles Cerebro-Oculo-Facio-Skeletal (COFS) syndrome, but it differs in the lack of the rapidly progressive neurologic features leading to severe brain atrophy with calcifications. Patients with MICRO syndrome manifest frontal cortical dysplasia, hypoplasia of the corpus callosum, cortical blindness with optic atrophy, profound mental retardation, and progressive joint contractures with growth failure. COFS syndrome shares also many clinical and cellular similarities with Cockayne syndrome (CS), and cultured cells in both conditions demonstrate hypersensitivity to ultraviolet (UV) radiation due to impaired nucleotide excision repair (NER). NER studies in cultured fibroblasts from MICRO patients give normal results, so MICRO syndrome should be considered in children with features resembling COFS syndrome and CS, but who have normal NER. MICRO should be distinguished from other similar clinical disorders with normal NER by the presence of significant visual impairment and cortical blindness despite early surgery for congenital cataracts, frontal polymicrogyria, thin corpus callosum, and cortical atrophy by MRI.

Abnormalities, Multiple↗