An N‐terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy

Heterozygous loss‐of‐function mutations in the X‐linked gene CASK are associated with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) and ophthalmological disorders including optic nerve atrophy (ONA) and optic nerve hypoplasia (ONH). Recently, we have demonstrated that CASK ^(+/−) mice display ONH with 100% penetrance but exhibit no change in retinal lamination or structure. It is not clear if CASK loss‐of‐function predominantly affects retinal ganglion cells, or if other retinal cells like photoreceptors are also involved. Here, we report a heterozygous missense mutation in the N‐terminal calcium/calmodulin‐dependent kinase (CaMK) domain of the CASK protein in which a highly conserved leucine is mutated to the cyclic amino acid proline. In silico analysis suggests that the mutation may produce destabilizing structural changes. Experimentally, we observe pronounced misfolding and insolubility of the CASK^L209P protein. Interestingly, the remaining soluble mutant protein fails to interact with Mint1, which specifically binds to CASK's CaMK domain, suggesting a mechanism for the phenotypes observed with the CASK^L209P mutation. In addition to microcephaly, cerebellar hypoplasia and delayed development, the subject with the L209P mutation also presented with bilateral retinal dystrophy and ONA. Electroretinography indicated that rod photoreceptors are the most prominently affected cells. Our data suggest that the CASK interactions mediated by the CaMK domain may play a crucial role in retinal function, and thus, in addition to ONH, individuals with mutations in the CASK gene may exhibit other retinal disorders, depending on the nature of mutation.

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The progression of Wiedemann–Steiner syndrome in adulthood and two novel variants in the KMT2A gene

Wiedemann–Steiner syndrome is a genetic condition associated with dysmorphic facies, hypertrichosis, short stature, developmental delay, and intellectual disability. Congenital malformations of the cerebral, cardiac, renal, and optic structures have also been reported. Because the majority of reported individuals with this condition have been under age 20, the long‐term prognosis is not well defined. Here we report on two further unrelated individuals diagnosed with Wiedemann–Steiner syndrome, one of whom is in her third decade of life. In addition, both individuals have novel KMT2A mutations. The information provided below about the outcome in Wiedemann–Steiner syndrome is important for families of affected individuals.

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A case of YY1‐associated syndromic learning disability or Gabriele‐de Vries syndrome with myasthenia gravis

Abstract

Exome sequencing is being used increasingly to evaluate patients with intellectual disability. YY1 is a ubiquitously distributed transcription factor belonging to the GLIKruppel class of zinc finger proteins recently recognized as the causative gene in 23 patients for the Gabriele‐de Vries syndrome. We report a new case with similar features and a novel variant in YY1, in a region of the gene, which has not previously been reported. A 25 year old female was referred to clinical genetics with a diagnosis of autoimmune myasthenia gravis, facial dysmorphism and learning disability. Chromosomal microarray and gene panel test for congenital myasthenic syndrome was negative. Whole exome sequencing (WES) revealed a presumed pathogenic de novo novel, heterozygous, truncating variant in the YY1 gene, c.860_864delTTAAAA, p.Ile287Argfs*3. The Ile287 residue is conserved across species and is situated in the transcription repressor domain of the protein. This variant is novel and lies in a domain of the protein where no previously reported variants occur. The phenotypic features of our case closely match those of the reported patients. Autoimmune myasthenia gravis has not been reported in these patients and may constitute an expansion of this phenotypic spectrum or perhaps more likely a second unrelated diagnosis.

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A homozygous MITF mutation leads to familial Waardenburg syndrome type 4

Waardenburg syndrome (WS) is a genetic disorder characterized by hearing loss and pigmentary abnormalities with variable penetrance. Though heterozygous mutations in MITF are a major cause for Waardenburg syndrome type 2 (WS2), homozygous mutations in this gene and the associated phenotype have been rarely characterized. In this study, we identified a novel p.R223H mutation in MITF in a Chinese Han family with variable WS features. Both parents carried a heterozygous p.R223H mutation. They had normal hearing, and premature greying of the hair is their only pigmentary abnormality. In contrast, their two children both carried a homozygous p.R223H mutation and had classic WS features including profound hearing loss, heterochromia irides and marked pigmentary abnormalities in hair and skin. Interestingly, the two affected children also have persistent chronic constipation since the neonatal period, symptoms suggestive of Waardenburg syndrome type 4 (WS4). Our study revealed a likely association between homozygous mutations in MITF and WS4, which implies a dosage effect for the underlying pathogenesis mechanism.

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High risk of spontaneous preterm birth among infants with gastroschisis

We examined the association between gastroschisis and preterm birth (PTB, <37 weeks) by subtype. The sample was drawn from singleton live births in California from 2007 to 2012 contained in a birth cohort file maintained by the California Office of Statewide Health Planning and Development (n = 2,891,965; 1,421 with gastroschisis). Relative risks (RRs) and 95% confidence intervals (CIs) were calculated for PTB by gestational age (<34, 34–36, and any <37 weeks) and by type (spontaneous labor with intact membranes, preterm premature rupture of the membranes [PPROM], provider initiated) and were adjusted for maternal characteristics. Over 44.5% of infants with gastroschisis were born preterm because of spontaneous etiologies; notably, 8.4% of infants with gastroschisis were born <34 weeks because of spontaneous etiologies (adjusted RRs 9.1–12.2). Overall, 53.7% of infants with gastroschisis were born preterm compared with only 6.9% of infants without gastroschisis (adjusted RR 15.2, 95% CI 13.6–19.5) and are at particularly high risk of spontaneous PTB. Nearly 9% of infants with gastroschisis delivered <34 weeks, regardless of preterm etiology, indicating that these infants are at great risk for PTB morbidities in addition to the complications from gastroschisis.

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A novel autosomal dominant mutation in SOX18 resulting in a fatal case of hypotrichosis–lymphedema–telangiectasia syndrome

Hypotrichosis–lymphedema–telangiectasia syndrome (HLTS) is a rare disorder caused by autosomal recessive and autosomal dominant mutations in SOX18. This gene encodes a transcription factor involved in the regulation and development of the human vasculature, lymphatic, and integumentary systems. Individuals with HLTS develop varying degrees of hypotrichosis, lymphedema, and telangiectasias. Other complications, such as renal failure and aortic dilation, have also been observed. Here, we report a neonate with a novel mutation in SOX18 (c.541C>T; p.Gln181stop) presenting with cardinal features of HLTS in addition to unique findings of severe chylothorax and relentless pulmonary hypertension that culminated in death. The purpose of this report is to summarize what is known about this evolving genetic syndrome and to speculate as to how mutations in SOX18 might produce the phenotype.

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GPR126: A novel candidate gene implicated in autosomal recessive intellectual disability

Intellectual disability (ID), a genetically and clinically heterogeneous disorder, affects 1%–3% of the general population and is a major health problem, especially in developing countries and in populations with a high frequency of consanguineous marriage. Using whole exome sequencing, a homozygous missense variation (c.3264G>C, p.W1088C) in a plausible disease causing gene, GPR126, was identified in two patients presenting with profound ID, severe speech impairment, microcephaly, seizures during infancy, and spasticity accompanied by cerebellar hypoplasia. The role of GPR126 in radial sorting and myelination in Schwann cells suggests a mechanism of pathogenesis for ID. Involvement of GPR126 in lethal congenital contracture syndrome 9 has been identified previously, but this is the first report of a plausible candidate gene, GPR126, in ID.

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