Molecular Support for Heterogonesis Resulting in Sesquizygotic Twinning.

Sesquizygotic multiple pregnancy is an exceptional intermediate between monozygotic and dizygotic twinning. We report a monochorionic twin pregnancy with fetal sex discordance. Genotyping of amniotic fluid from each sac showed that the twins were maternally identical but chimerically shared 78% of their paternal genome, which makes them genetically in between monozygotic and dizygotic; they are sesquizygotic. We observed no evidence of sesquizygosis in 968 dizygotic twin pairs whom we screened by means of pangenome single-nucleotide polymorphism genotyping. Data from published repositories also show that sesquizygosis is a rare event. Detailed genotyping implicates chimerism arising at the juncture of zygotic division, termed heterogonesis, as the likely initial step in the causation of sesquizygosis.

Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency.

BACKGROUND: Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known. OBJECTIVE: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease. METHODS: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. RESULTS: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes. CONCLUSION: ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.

Waiting for a diagnosis in Rubinstein-Taybi: The journey from "ignorance is bliss" to the value of "a label".

The journey to receiving a diagnosis for rare genetic disease can be long and emotionally impactful. This study describes parental experiences of receiving their child's diagnosis of Rubinstein-Taybi syndrome (RTS), a rare genetic condition characterized by growth and developmental delay together with dysmorphic features. Parents from the RTS Australia support group participated in qualitative, semi-structured phone interviews, which were transcribed verbatim and thematically analyzed. Questions focused on psychosocial challenges and benefits pre and post-diagnosis. Ten mothers and three fathers participated, with the mean age of diagnosis being 8 months. Parents reported positive psychological effects from a slight delay in diagnosis, and negative effects from an extended diagnostic delay, suggesting the ideal time for a parent to receive a diagnosis lies in the post attachment stage, prior to the development of significant parental concerns. This stage would vary depending on condition severity. Parents desired a diagnosis to reduce uncertainty; however, uncertainty remained post diagnosis, and shifted its focus from broadly encompassing etiology and prognosis, to specifically focusing on concerns regarding severity within the spectrum. Perceived benefits of a diagnosis mainly centered on the provision of a label. Parents articulated that a label increased social acceptance, enhanced coping, promoted communication, and improved access to medical, financial, and support services. This study provides insights into the experience of families prior to and following receipt of a diagnosis. It also highlights the possibility of an optimal time window to receive a diagnosis; in which bonding is maximized and parental distress is minimized.

Severe hypertension-An infantile feature of Jansen metaphyseal chondrodysplasia?

Jansen metaphyseal chondrodysplasia (JMC) is a rare autosomal dominant skeletal dysplasia caused by gain-of-function mutations in the parathyroid hormone receptor 1 gene, PTH1R. We report on a patient presenting in the neonatal period with clinical signs of JMC in addition to severe hypertension. A pathogenic mutation in PTH1R was demonstrated, but investigations for hypertension yielded normal results. Hypertension has not been previously associated with JMC. Given aberration of the parathyroid hormone (PTH)/parathyroid-related protein pathway is the underlying pathogenic mechanism attributed to JMC, and also given evidence that hyperparathyroidism plays an important role in blood pressure homeostasis, we propose that hypertension is a hitherto unrecognized feature of JMC.

Human Genetics Society of Australasia Position Statement: Genetic Testing and Personal Insurance Products in Australia.

The expansion of genetic and genomic testing in clinical practice and research and the growing market for at home personal genome testing has led to increased awareness about the impact of this form of testing on insurance. Genetic or genomic information can be requested by providers of mutually rated insurance products, who may then use it when setting premiums or determining eligibility for cover under a particular product. Australian insurers are subject to relevant legislation and an industry standard that was updated in late 2016. In 2018, the Human Genetics Society of Australasia updated its position statement on genetic testing and life insurance to account for these changes and to increase the scope of the statement to include a wider scope of insurance products that are not rated according to community risk, such as life, critical care, and income protection products. Recommendations include that providers of professional education involving genetics should include ethical, legal, and social aspects of insurance discrimination in their curricula; that the Australian government take a more active role in regulating use of genetic information in personal insurance, including enacting a moratorium on use of genetic test results; that information obtained in the course of a research project be excluded; and that there is improved engagement between the insurance industry, regulators, and the genetics profession.

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy.

Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy.

Expanding the genotypic spectrum of CCBE1 mutations in Hennekam syndrome.

Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder, with 25% of patients having mutations in CCBE1. We identified a family with two brothers presenting with primary lymphedema, and performed exome sequencing to determine the cause of their disease. Analysis of four family members showed that both affected brothers had the same rare compound heterozygous mutations in CCBE1. The presumed paternally inherited NM_133459.3:c.310G>A; p.(Asp104Asn), lies adjacent to other known pathogenic CCBE1 mutations, while the maternally inherited NM_133459.3:c.80T>C; p.(Leu27Pro) lies in the CCBE1 signal peptide, which has not previously been associated with disease. Functional analysis in a zebrafish model of lymphatic disease showed that both mutations lead to CCBE1 loss of function, confirming the pathogenicity of these variants and expanding the genotypic spectrum of lymphatic disorders. © 2016 Wiley Periodicals, Inc.

The congenital hearing phenotype in GJB2 in Queensland, Australia: V37I and mild hearing loss predominates.

GJB2 was originally identified in severe, non-syndromic sensorineural hearing loss (SNHL), but was subsequently associated with mild and moderate SNHL. Given the increasing utilisation of genetic testing pre-conceptually, prenatally, and neonatally, it is crucial to understand genotype-phenotype correlations. This study evaluated the nature and frequency of GJB2 variants in an Australian paediatric population with varying degrees of SNHL ascertained through newborn hearing screening. Audiograms from individuals with GJB2 variants and/or a GJB6 deletion (GJB6-D13S11830) were retrospectively reviewed (n = 127). Two-thirds were biallelic (homozygous/compound heterozygous) for pathogenic/likely pathogenic variants of GJB2 and/or GJB6 (n = 80). The most frequent variant was c.109 G > A, followed by c.35delG and c.101 T > C. Compared to biallelic carriage of other GJB2 variants, c.109 G > A positive individuals (homozygous/compound heterozygous) were more likely to have mild HL at their initial and latest audiograms (p = 0.0004). Biallelic carriage of c.35delG was associated with moderately-severe or greater SNHL at both initial and latest audiograms (p = 0.007). The c.101 T > C variant presented with milder SNHL and U-shaped audiograms (p = 0.02). In this agnostically identified cohort, mild SNHL predominated in GJB2/GJB6 carriers in contrast to previous studies targeting individuals with significant loss. Consequently, c.109 G > A, associated with milder phenotypes, was the most frequent. This study provides valuable data to support prognostic confidence in genetic counselling.

Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay.

Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis.

Mutation update for the PORCN gene.

Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then, several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum, the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on seven new mutations together with the corresponding clinical data. Based on the review we have created a Web-based locus-specific database that lists all identified variants and allows the inclusion of future reports. The database is based on the Leiden Open (source) Variation Database (LOVD) software, and is accessible online at http://www.lovd.nl/porcn. At present, the database contains 106 variants, representing 68 different mutations, scattered along the whole coding sequence of the PORCN gene, and 12 large gene rearrangements, which brings up to 80 the number of unique mutations identified in Goltz-Gorlin syndrome patients.

Temple-Baraitser syndrome: a rare and possibly unrecognized condition.

Temple-Baraitser syndrome, previously described in two unrelated patients, is the association of severe mental retardation and abnormal thumbs and great toes. We report two additional unrelated patients with Temple-Baraitser syndrome, review clinical and radiological features of previously reported cases and discuss mode of inheritance. Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. All patients were born to unrelated parents and occurred as a single occurrence in multiple sibships, suggesting sporadic inheritance from a de novo mutation mechanism. Comparative genomic hybridization in Patients 1, 2 and 3 did not reveal any copy number variations. We confirm that Temple-Baraitser syndrome represents a distinct syndrome, probably unrecognized, possibly caused by a de novo mutation in a not yet identified gene.

A second case of severe mental retardation and absent nails of hallux and pollex (Temple-Baraitser syndrome).

We present a case of a male with severe mental retardation, seizure disorder, and absence/hypoplasia of the thumb and great toe nails. This combination of clinical findings has been reported only once previously. We suggest it represents a distinct syndrome. Our case has the additional finding of broad thumbs.

Characterizing the oculoauriculofrontonasal syndrome.

Human dysmorphology syndromes are frequently defined by characteristic abnormalities in facial morphogenesis. Two such well recognized syndromes are the oculoauriculovertebral spectrum (OAVS) and frontonasal dysplasia (FND). OAVS is diagnosed on the basis of the presence of typical facial features which can include microtia, preauricular tags, hemifacial microsomia, lateral face clefting, epibulbar dermoids, and upper palpebral colobomata. FND is characterized by ocular hypertelorism, nasal clefting, and anterior cranium bifidum occultum. After the first patient was described with features of both OAVS and FND, at least a further 25 patients presenting the 'oculoauriculofrontonasal syndrome' (OAFNS) have been reported. We report on four more patients with OAFNS and review their features, together with those of the other patients reported in the medical literature. We suggest that, statistically, OAFNS is more likely to be a sporadically occurring condition rather than an inherited autosomal recessive trait, as previously suggested. We cannot, however, definitively exclude the possibility of autosomal dominant transmission. Considering the question of whether OAFNS is a part of OAVS, FND, or a distinct clinical entity, we conclude that, for the time being, OAFNS should be considered to be a distinct syndrome, to further our understanding of the aetiology of these conditions.

Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.

Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.

The oculoauriculovertebral spectrum: Refining the estimate of birth prevalence.

The oculoauriculovertebral spectrum (OAVS) is a well-described pattern of congenital malformations primarily characterized by hemifacial microsomia and/or auricular dysplasia. However, the birth prevalence of OAVS is poorly characterized. Figures ranging from 1 in 150,000 through to 1 in 5,600 can be found in the literature - the latter figure being the most frequently quoted. This study aims to evaluate the reasons behind such discrepant figures and to refine the estimated birth prevalence of OAVS. Published reports on the incidence and prevalence of OAVS were systematically sought after. This evidence was critically reviewed. Data from appropriate studies was amalgamated to refine the estimate of the birth prevalence for OAVS. Two main reasons were identified why birth prevalence figures for OAVS are so highly discrepant: differing methods of case ascertainment and the lack of a formal definition for OAVS. This study refines the estimate of birth prevalence for OAVS to between 1 in 40,000 and 1 in 30,000. This number needs to be confirmed in a large well-designed prospective study using a formally agreed-upon definition for OAVS.

Neonatal severe hyperparathyroidism: an important clue to the aetiology.

Neonatal severe hyperparathyroidism is a rare condition that presents as striking hyperparathyroidism, hypercalcaemia, and metabolic bone disease. The aetiology needs to be determined soon after diagnosis to direct appropriate management and to determine an accurate prognosis. Taking a family history is a valuable clinical tool in paediatric medicine. Presented here is the case of a neonate presenting with severe hyperparathyroidism. Obtaining the family history, coupled with basic parental studies, enabled a rapid aetiological diagnosis, which allowed for conservative management.