Hereditary Spherocytosis Caused by a Novel Compound Heterozygous Mutation of the SPTA1 Gene and Autoimmune Hepatitis in a Pediatric Patient

Objective: Patients suffering from both hereditary spherocytosis (HS) and autoimmune hepatitis (AIH) are very rare. We analyzed the clinical and genetic characteristics of a seven-year-old girl with yellow sclerae and abnormal liver function tests, but no further symptoms. Methods: Blood samples were collected from the proband, her parents, and her paternal grandmother, and analyzed using routine laboratory tests, as well as subjected to next-generation and Sanger sequencing.Results: Compound heterozygous mutations of the spectrin alpha, erythrocytic 1 (SPTA1) gene were identified in the proband. Thec.134G>A (p.R45K) and c.6544G>C (p.D2182H) mutations were inherited from her mother and father, respectively. The proband’s father and paternal grandmother had the same mutation. Neither mutation is described in the Human Gene Mutation Database. Conclusions: HS has clinical manifestations similar to AIH, it may be difficult to diagnose when it coexists with AIH. When laboratory results cannot be explained by autoimmune liver disease alone, the possibility of a concomitant disease should be considered. Pedigree investigation and genetic analyses might be required to arrive at the final diagnosis.

Variable expressivity of BEST1-associated autosomal dominant vitreoretinochoroidopathy (ADVIRC) in a three-generation pedigree

ObjectiveAutosomal dominant vitreoretinochoroidopathy (ADVIRC) is associated with pathogenic variants in BEST1, which typically causes visual impairment in the late stage of disease. We present a pedigree with variable expressivity and the youngest case in the literature with visual impairment in early childhood.Methods and analysisThis is a retrospective, observational, case series describing multigenerational members of one family affected with ADVIRC. Patients underwent examination, ultra-widefield fundus photography and angiography, optical coherence tomography, full-field electroretinography (ffERG) and full-field perimetry.ResultsThree affected members of the pedigree, one from each successive generation, were found to harbour a mutation, c.715G>A:p.Val239Met, in BEST1. The proband characterised in this report is, to our knowledge, the youngest documented case of ADVIRC in early childhood. Yet, this patient has the most severe retinal dysfunction compared with the father and paternal grandmother, whom exhibit classic characteristics of ADVIRC. Longitudinal data from the paternal grandmother showed that there was a rapid decline in ffERG responses (photopic decline worse than scotopic) from the fourth to fifth decade of life, which correlated with severe concentric constriction of visual fields.ConclusionThis multigenerational case series provides new insights into the ADVIRC disease spectrum and rate of progression. While ADVIRC typically causes a slowly progressive disease, we show that variable phenotypic expressivity is possible among affected members of the same family with the same mutation in BEST1. Thus, ADVIRC must also be considered in the differential diagnosis of paediatric patients with severe retinal dystrophy in early childhood.

Grandparents childhood exposures and religious belief in their granddaughters: possible transgenerational associations

The prevalence of religious belief has fallen dramatically. A possible reason is that environmental exposures to previous generations are involved, e.g., evidence of an association between childhood exposures of grandparents and outcomes in their grandchildren including obesity, autistic traits, and survival have been reported. Generally, the associations between the grandparent’s exposure and grandchild’s outcome varied with sex of grandparent, his/her age at exposure and sex of the grandchild.Using data collected by the Avon Longitudinal Study of Parents and Children (ALSPAC) we investigate whether exposures such as smoking and/or traumatic events experienced by any of the grandparents are associated with the likelihood that their adult grandchildren have a religious belief. We show that the granddaughters (but not the grandsons) were more likely to have reported such a belief if one of their maternal grandparents had experienced traumatic events pre-puberty (age 6-11), or their paternal grandmother had experienced such events in adolescence. Conversely if their maternal grandfather had started smoking regularly during childhood or their paternal grandmother had smoked prenatally, the granddaughter was substantially less likely to be a believer. These associations were mutually independent and not explained by demographic factors. They may account for a small proportion of the fall in prevalence of religious belief over time, but the association needs confirming in other studies.

Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database

Malignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband’s paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.

Controversy on the Management of Patients Carrying RET p.V804M Mutation

Context: RET p.V804M is classified as a moderate-risk mutation for familial medullary thyroid cancer (FMTC). There is a significant controversy on the management of patients carrying this mutation. We describe a family incidentally discovered to have this mutation during evaluation of a newborn with dysmorphic features. We provide a comprehensive literature review of RET p.V804M mutation. Results: The proband was born to a first-degree relative parents with hypertrophy of some parts of the body and vascular skin changes. Whole exome sequencing of DNA extracted from a skin biopsy showed a mutation in the PIK3CA (c.3132T>G, p.ASN1044LYS). This variant was not found in DNA extracted from blood. This confirmed the diagnosis CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis, skeletal or spinal anomalies). Another incidentally found mutation in the skin biopsy and blood sample was RET p.V804M. Although there was no family history of MTC or MEN 2 syndromes, family screening revealed RET p.V804M mutation and FMTC in the proband's father, paternal grandmother, one sister and one aunt. There was significant interfamilial heterogeneity in age of presentation and pathology. Review of data showed that RET p.V804M mutation is an indolent mutation that may be discovered incidentally and associated with low risk of FMTC, usually at middle to old age. Conclusion: This and other recent studies raise questions about whether the American Thyroid Association (ATA) guidelines for management of patients with moderate risk RET mutations should also be applied to this seemingly “low” risk RET p.V804M mutation.

Ancestral smoking and developmental outcomes: A review of publications from a population birth cohort

The adverse effects on the child of maternal smoking in pregnancy is well-recognised, but little research has been carried out on the possible non-genetic effects of ancestral smoking prior to the pregnancy including parental initiation of cigarette smoking in their own childhoods or a grandmother smoking during pregnancy. Here we summarise the studies that have been published mainly using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We demonstrate evidence that ancestral smoking prior to or during pregnancy can often be beneficial for offspring health and both ancestor- and sex-specific. More specifically, we report evidence of (i) adverse effects of the father starting to smoke pre-puberty on his son’s development; (ii) beneficial effects on the grandson if his maternal grandmother had smoked in pregnancy; and (iii) mainly adverse effects on the granddaughter when the paternal grandmother had smoked in pregnancy. The ancestor- and sex-specificity of these results is consistent with earlier studies reporting associations of health and mortality with ancestral food supply in their parents’ and grandparents’ pre-pubertal childhoods.

Grandchild’s IQ is associated with grandparental environments prior to the birth of the parents

Background. Despite convincing animal experiments demonstrating the potential for environmental exposures in one generation to have demonstrable effects generations later, there have been few relevant human studies. Those that have been undertaken have demonstrated associations, for example, between exposures such as nutrition and cigarette smoking in the grandparental generation and outcomes in grandchildren. We hypothesised that such transgenerational associations might be associated with the IQ of the grandchild, and that it would be likely that there would be differences in results between the sexes of the grandparents, parents, and children. Method. We used three-generational data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We incorporated environmental factors concerning grandparents (F0) and focussed on three exposures that we hypothesised may have independent transgenerational associations with the IQ of the grandchildren (F2): (i) UK Gross Domestic Product (GDP) at grandparental birth year; (ii) whether grandfather smoked; and (iii) whether the grandmother smoked in the relevant pregnancy. Potential confounders were ages of grandparents when the relevant parent was born, ethnic background, education level and social class of each grandparent. Results. After adjustment, all three target exposures had specific associations with measures of IQ in the grandchild. Paternal grandfather smoking was associated with reduced total IQ at 15 years; maternal grandfather smoking with reduced performance IQ at 8 years and reduced total IQ at 15. Paternal grandmother smoking in pregnancy was associated with reduced performance IQ at 8, especially in grandsons. GDP at grandparents’ birth produced independent associations of reduced IQ with higher GDP; this was particularly true of paternal grandmothers. Conclusions. These results are complex and need to be tested in other datasets. They highlight the need to consider possible transgenerational associations in studying developmental variation in populations.

Offspring fertility and grandchild survival enhanced by maternal grandmothers in a pre-industrial human society

Help is directed towards kin in many cooperative species, but its nature and intensity can vary by context. Humans are one of few species in which grandmothers invest in grandchildren, and this may have served as an important driver of our unusual life history. But helping behaviour is hardly uniform, and insight into the importance of grandmothering in human evolution depends on understanding the contextual expression of helping benefits. Here, we use an eighteenth-nineteenth century pre-industrial genealogical dataset from Finland to investigate whether maternal or paternal grandmother presence (lineage relative to focal individuals) differentially affects two key fitness outcomes of descendants: fertility and survival. We found grandmother presence shortened spacing between births, particularly at younger mother ages and earlier birth orders. Maternal grandmother presence increased the likelihood of focal grandchild survival, regardless of whether grandmothers had grandchildren only through daughters, sons, or both. In contrast, paternal grandmother presence was not associated with descendants’ fertility or survival. We discuss these results in terms of current hypotheses for lineage differences in helping outcomes.

Losing Black Mothers, Finding Revolutionary Mothering

My mother is losing her mother to Alzheimer's disease. Although my mother feels loss, I am connecting through my (maternal) grandmother to our ancestors, including a deceased father and paternal grandmother. I am also connecting to a daughter who has lost her mother, through a (maternal) grandmother who, through her loss of memory, is more open to kin networks than my mother. Through deepening connections to my maternal grandmother and to my daughter, I feel I am losing my mother. I look to revolutionary mothering as a way to reconnect shattered bonds and find lost mothers. This article honors the important work of Saidiya Hartman, Dorothy Roberts, and countless revolutionary mothers.

“The work of a leader is to carry the bones of the people”: exploring female-led articulation of Indigenous knowledge in an urban setting

Although the activism and historic contributions of Indigenous female leaders to urban Indigenous community development across Turtle Island are recognized, there remains a dearth in the literature regarding the specific mechanisms that enabled Indigenous women to successfully articulate cultural knowledge and inform their management styles by traditional ways. The article explores some of the contributions of female leadership to the governance and program design of a large, culture-based urban Indigenous non-governmental organization in Canada—the Ontario Federation of Indigenous Friendship Centres (OFIFC). We examine how the OFIFC’s Executive Director Sylvia Maracle (Skonaganleh:ra) has applied leadership principles grounded in Indigenous knowledge of her paternal grandmother and a Mohawk matriarch—Mary Ellen Maracle—to address specific challenges in urban Indigenous governance. We argue that the female-led articulation of Indigenous knowledge in organizational operations contributed to creating a community of service that respects distinct expressions of cultural and gender identity.