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Lessons from a pair of siblings with BPAN.

ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered.

SUBMITTER: Zarate YA

PROVIDER: S-EPMC5070893 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Lessons from a pair of siblings with BPAN.

Zarate Yuri A YA Jones Julie R JR Jones Melanie A MA Millan Francisca F Juusola Jane J Vertino-Bell Annette A Schaefer G Bradley GB Kruer Michael C MC

European journal of human genetics : EJHG 20151118 7

Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality ...[more]

PMID: 26577041

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Project description:BackgroundBeta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes.MethodsA total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2.ResultsOverall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests.ConclusionOur data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.

Project description:Multi-configuration pair-density functional theory (MC-PDFT) has proved to be a powerful way to combine the capabilities of multi-configuration self-consistent-field theory to represent the an electronic wave function with a highly efficient way to include dynamic correlation energy by density functional theory. All applications reported previously involved complete active space self-consistent-field (CASSCF) theory for the reference wave function. For treating large systems efficiently, it is necessary to ask whether good accuracy is retained when using less complete configuration interaction spaces. To answer this question, we present here calculations employing MC-PDFT with the separated pair (SP) approximation, which is a special case (defined in this article) of generalized active space self-consistent-field (GASSCF) theory in which no more than two orbitals are included in any GAS subspace and in which inter-subspace excitations are excluded. This special case of MC-PDFT will be called SP-PDFT. In SP-PDFT, the electronic kinetic energy and the classical Coulomb energy, the electronic density and its gradient, and the on-top pair density and its gradient are obtained from an SP approximation wave function; the electronic energy is then calculated from the first two of these quantities and an on-top density functional of the last four. The accuracy of the SP-PDFT method for predicting the structural properties and bond dissociation energies of twelve diatomic molecules and two triatomic molecules is compared to the SP approximation itself and to CASSCF, MC-PDFT based on CASSCF, CASSCF followed by second order perturbation theory (CASPT2), and Kohn-Sham density functional theory with the PBE exchange-correlation potential. We show that SP-PDFT reproduces the accuracy of MC-PDFT based on the corresponding CASSCF wave function for predicting C-H bond dissociation energies, the reaction barriers of pericyclic reactions and the properties of open-shell singlet systems, all at only a small fraction of the computational cost.

Project description:ObjectiveTo explore the risk of colorectal cancer in family members of patients with colorectal cancer, with an emphasis on subtypes of second degree relatives, especially half siblings, which were lacking in the literature.DesignAmbidirectional cohort study.SettingNationwide Swedish Family Cancer Data (record linkage).ParticipantsAll people residing in Sweden and born after 1931, with their biological parents, totalling >16 million individuals (follow-up: 1958-2015); of those with clear genealogy, 173 796 developed colorectal cancer.Main outcome measuresLifetime (0-79 years) cumulative risk and standardised incidence ratio of colorectal cancer among first degree relatives and second degree relatives.ResultsThe overall lifetime cumulative risk of colorectal cancer in siblings of patients was 7%, which represents a 1.7-fold (95% confidence interval 1.6 to 1.7; n=2089) increase over the risk in those without any family history of colorectal cancer. A similarly increased lifetime cumulative risk (6%) was found among half siblings (standardised incidence ratio 1.5, 95% confidence interval 1.3 to 1.8; n=140). The risk in people with colorectal cancer in both a parent and a half sibling (standardised incidence ratio 3.6, 2.4 to 5.0; n=32) was close to the risk in those with both an affected parent and an affected sibling (2.7, 2.4 to 3.0; n=396). Family history of colorectal cancer in only one second degree relative other than a half sibling (without any affected first degree relatives), such as a grandparent, uncle, or aunt, showed minor association with the risk of colorectal cancer.ConclusionFamily history of colorectal cancer in half siblings is similarly associated with colorectal cancer risk to that in siblings. The increase in risk of colorectal cancer among people with one affected second degree relative was negligible, except for half siblings, but the risk was substantially increased for a combination of family history in one affected second degree relative and an affected first degree relative (or even another second degree relative). These evidence based findings provide novel information to help to identify people at high risk with a family history of colorectal cancer that can potentially be used for risk adapted screening.

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Lessons from a pair of siblings with BPAN.

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Lessons from a pair of siblings with BPAN.

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