Parental Somatic Mosaicism Uncovers Inheritance of an Apparently De Novo GFAP Mutation

Alexander disease is a leukodystrophy caused by heterozygous mutations of GFAP gene. Recurrence in siblings from healthy parents provides a confirmation to the transmission of variants through germinal mosaicism. With the use of DNA isolated from peripheral blood, next-generation sequencing (NGS) of GFAP locus was performed with deep coverage (≥500×) in 11 probands and their parents (trios) with probands heterozygous for apparently de novo GFAP mutations. Indeed, one parent had somatic mosaicism, estimated in the range of 8.9%–16%, for the mutant allele transmitted to the affected sibling. Parental germline mosaicism deserves attention, as it is critical in assessing the risk of recurrence in families with Alexander disease.

My Sister’s Keeper: Survivors Disclosing Sexual Violence to a Sibling

Siblings are often cited as a source of support throughout life, but they have not been included in studies of sexual violence disclosure. Survivors of sexual violence often delay or do not disclose their sexual violence. The current study investigated if and why survivors of sexual violence decided to disclose to their sibling. This qualitative investigation included 10 female participants, of which six had disclosed their abuse to their sibling. The participants ranged in age from 20 to 58, five identified as Hispanic, one as Hispanic and White three identified as White, and one identified as Middle Eastern. Thematic analysis was used to examine the data. Three major themes were identified that affected sibling disclosure decisions: sibling dynamics, perceived and real reactions to disclosure, and words of advice. The findings from this study demonstrate the continued need to investigate siblings and their role in disclosure of sexual violence. Practitioners may also want to examine the sibling relationship as a source of support for survivors of sexual violence. Finally, as policies continue to develop around support of survivors of sexual violence, inclusion of siblings in family policies, outreach centers, and counseling services may be beneficial.

A Novel Recessive PDZD7 Bi-Allelic Mutation in an Iranian Family with Non-Syndromic Hearing Loss

BackgroundAutosomal recessive non-syndromic hearing loss (ARNSHL) is genetically and phenotypically heterogeneous with over 110 genes causally implicated in syndromic and non-syndromic hearing loss (HL). Here, we investigate the genetic etiology of deafness in twoGJB2 and GJB6 negative patients presenting with pre-lingual, progressive, severe hearing loss.MethodsTargeted exome sequencing (TES) using Next Generation Illumina Sequencing was used to analyze the exonic and some other important genomic regions of 154 genes in the proband. Subsequently, the mutation found was confirmed by Sanger sequencing in other affected sibling and healthy family members. The possible impact of the reported mutation on the corresponding protein was also evaluated by using bioinformatics tools. Moreover, the affected patients underwent audiological and ophthalmic evaluations.ResultsTES identified a novel homozygous missense mutation c.251T>C (p.I84T) in exon 3 of PDZD7 gene. In addition, segregation and phenotype-genotype correlation analysis as well as in-silico evaluations confirmed the autosomal recessive inheritance pattern and disease-causing nature of mutation found. ConclusionsIn overall, our finding could expand the pathogenic mutations spectrum and strengthens the clinical importance of the PDZD7 gene in ARNSHL patients. It can also aid to conduct genetic counseling, prenatal diagnosis and clinical management of these types of genetic disorders.

Within-Family Validation of Polygenic Risk Scores and Complex Trait Prediction

We test a variety of polygenic predictors using tens of thousands of genetic siblings for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in within-family designs. In the case of disease risk we test the extent to which higher polygenic risk score (PRS) identifies the affected sibling, and also compute Relative Risk Reduction as a function of risk score threshold. For quantitative traits we examine between-sibling differences in trait values as a function of predicted differences, and compare to performance in non-sibling pairs. Example results: Given 1 sibling with normal-range PRS score (<84 percentile) and 1 sibling with high PRS score (top few percentiles), the predictors identify the affected sibling about 70-90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc. For height, the predictor correctly identifies the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.

Nephrogenic Diabetes Insipidus - A Rare Report of Two Affected Sibling

Nephrogenic Diabetes Insipidus (NDI) is a type of Diabetes Insipidus (DI) where distal nephrons are unresponsive to antidiuretic hormone resulting in polyuria and polydipsia. NDI can be congenital or acquired. There are very few cases of congenital NDI, more in sibs. Here we report two sibs affected with congenital NDI. Both of them presented with polyuria, polydipsia and failure to thrive since early infancy. In both cases, water deprivation tests and urine osmolality were done before and after DDAVP that suggested NDI and the acquired causes has been excluded. Both of them were treated with oral Hydrochlorothiazide and improved.Bangladesh J Child Health 2017; VOL 41 (3) :193-195

Offspring genes indirectly influence sibling and maternal behavioural strategies over resource share

Family members show behavioural strategies predicted to maximize individual fitness. These behaviours depend directly on genes expressed in focal individuals but also indirectly on genes expressed in other family members. However, how sibling and parental behavioural strategies are modified by genes expressed in family members, and to what degree, remains unclear. To answer this question, we have used a split litter design in an experimental population of genetically variable mouse families, and identified loci that indirectly affected sibling and maternal behaviour simultaneously. These loci map to genomic regions that also show a direct effect on offspring behaviour. Directly and indirectly affected traits were significantly correlated at the phenotypic level, illustrating how indirect effects are caused. Genetic variants in offspring that influence solicitation also impacted their siblings' and maternal behaviour. However, in contrast to predictions from sibling competition, unrelated litter mates benefited from increased solicitation. Overall, such indirect genetic effects explained a large proportion of variation seen in behaviours, with candidate genes involved in metabolism to neuronal development. These results reveal that we need to view behavioural strategies as the result of conjoint selection on genetic variation in all interacting family members.

Could Congenital Insensitivity to Pain with Anhidrosis Be Misdiagnosed as Papillon–Lefèvre Syndrome?

Papillon–Lefèvre syndrome (PLS) is a rare autosomal recessive disorder characterized by early loss of teeth with hyperkeratosis of the palms and soles. Congenital insensitivity to pain with anhidrosis (CIPA) is a disorder of decreased pain sensation, decreased sweating, recurrent infections, and fever. Here, we report a 5-year-old girl born to consanguineous parents with a family history of a similarly affected sibling. The girl presented with early loss of teeth and palmoplantar hyperkeratosis, hence, provisionally diagnosed as PLS. Further clinical examination and detailed history taking shifted the diagnosis to CIPA. CIPA could be misdiagnosed as PLS. Congenital insensitivity to pain with anhidrosis, although rare, should be considered in the differential diagnosis of PLS.

Age at fatherhood: heritability and associations with psychiatric disorders

BackgroundAdvancing paternal age has been linked to psychiatric disorders. These associations might be caused by the increased number of de novo mutations transmitted to offspring of older men. It has also been suggested that the associations are confounded by a genetic liability for psychiatric disorders in parents. The aim of this study was to indirectly test the confounding hypotheses by examining if there is a genetic component to advancing paternal age and if men with a genetic liability for psychiatric disorders have children at older ages.MethodWe examined the genetic component to advancing paternal age by utilizing the twin model in a cohort of male twins (N = 14 679). We also studied ages at childbirth in men with or without schizophrenia, bipolar disorder and/or autism spectrum disorder. Ages were examined in: (1) healthy men, (2) affected men, (3) healthy men with an affected sibling, (4) men with healthy spouses, (5) men with affected spouses, and (6) men with healthy spouses with an affected sibling.ResultsThe twin analyses showed that late fatherhood is under genetic influence (heritability = 0.33). However, affected men or men with affected spouses did not have children at older ages. The same was found for healthy individuals with affected siblings. Instead, these men were generally having children at younger ages.ConclusionAlthough there is a genetic component influencing late fatherhood, our data suggest that the associations are not explained by psychiatric disorders or a genetic liability for psychiatric disorders in the parent.