Functional Analysis of a De Novo ACTB Mutation in a Patient with Atypical Baraitser–Winter Syndrome

Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We report a patient presenting with microcephaly, dysmorphic features, and intellectual disability with a tentative diagnosis of Dubowitz syndrome. Exome analysis was performed on the patient and both parents. A de novo missense variant was identified in ACTB, c.349G>A, p.E117K. Recent work in Baraitser–Winter syndrome has identified ACTB and ACTG1 mutations in a cohort of individuals, and we rediagnosed the patient with atypical Baraitser–Winter syndrome. We performed functional characterization of the variant actin and show that it alters cell adhesion and polymer formation supporting its role in disease. We present the clinical findings in the patient, comparison of this patient to other patients with ACTB/ACTG1 mutations, and results from actin functional studies that demonstrate novel functional attributes of this mutant protein.     

Prenatal presentation and diagnosis of Baraitser‐Winter syndrome using exome sequencing

Baraitser‐Winter cerebrofrontofacial syndrome (BWCFF) is a rare autosomal dominant developmental disorder associated with missense mutations in the genes ACTB or ACTG1. The classic presentation of BWCFF is discerned by the combination of unique craniofacial characteristics including ocular coloboma, intellectual disability, and hypertelorism. Congenital contractures and organ malformations are often present, including structural defects in the brain, heart, renal, and musculoskeletal system. However, there is limited documentation regarding its prenatal presentation that may encourage healthcare providers to be aware of this disorder when presented throughout pregnancy. Herein we describe a case of a pregnancy with large cystic hygroma and omphalocele. Whole exome sequencing (WES) was performed and a de novo, heterozygous, likely pathogenic mutation in ACTB was detected, c.1004G>A (p.Arg335His), conferring a diagnosis of BWCFF.     

Amniotic band sequence in paternal half‐siblings with vascular Ehlers–Danlos syndrome

Familial amniotic band sequence (ABS) is rare but has been reported in the offspring of mothers with connective tissue disorders. We present a family of two half‐siblings with ABS who share the same biological father. Following a serious vascular event a de novo pathogenic variant in COL3A1 was detected in the father, confirming a diagnosis of vascular Ehlers–Danlos syndrome (vEDS). The same variant was found in both his ABS‐affected children but not in his unaffected child. The amniotic membrane is derived from fetal tissue, type III collagen being a component. As the affected children are paternal half‐siblings, ABS was less likely due to maternal factors. Rather, the amniotic bands may have resulted from decreased type III collagen production as seen in people with vEDS, causing fragility of the amniotic membrane. Consequently, it is important to consider vEDS in patients with ABS.     

Autosomal dominant tibial hemimelia–polysyndactyly-triphalangeal thumbs syndrome: Report of a Brazilian family

We report on 3 persons in a 3-generation Brazilian family affected with complex limb defects. The spectrum of limb anomalies ranged from isolated toe syndactyly to severe bilateral tibial aplasia. Radioulnar synostosis was present in 2 of the 3 patients. Clinical and genetic aspects are discussed.     

Oral–facial–digital syndrome type VI (Váradi syndrome): Further clinical delineation

Cerebellar anomalies are consistent findings in patients with the oral–facial–digital syndrome type VI (Váradi syndrome) in addition to variable facial and oral changes, and polysyndactyly of hands and feet. We report 3 unrelated patients with this entity who have a hypoplastic cerebellar vermis shown by magnetic resonance imaging (MRI), as well as clinical signs of cerebellar defect. Polydactyly of the hands is characterized by a central Y-shaped metacarpal. Clinically recurrent episodes of tachypnea and hyperpnea are remarkable. Postnatal growth is delayed with short stature in all 3 patients possibly due to growth hormone deficiency in one of them. In contrast to reported patients who are all severely mentally retarded, one of our patients is of normal intelligence. Type VI oral-facial-digital syndrome is an autosomal-recessive trait and may be detected prenatally.     

Discordance of oral–facial–digital syndrome type 1 in monozygotic twin girls

The oral–facial–digital syndrome type 1 (OFD1) includes limb, facial, intraoral malformations and the gene for the disorder was recently mapped to Xp22.3-p22.2. We report on monozygotic twin girls discordant for OFD1. Monozygosity is supported by placental pathology (monochorionic diamniotic) and molecular studies with probability of dizygosity <1 × 10⁻⁶. The affected twin has oral cavity abnormalities including median cleft lip, cleft palate, lobulated hamartomatous tongue, aberrant hyperplastic oral frenula, alveolar notches, and absent lateral incisors. Facial manifestations include telecanthus, hypoplastic alae nasi, and transient neonatal facial milia. The patient also has short and deviated fingers with partial cutaneous syndactyly. At 10 years, she has not had central nervous system or kidney problems. X-inactivation study revealed similar X-inactivation patterns in the lymphoblasts of both twins. We conclude that skewed X-inactivation is an unlikely cause for the discordance, which is more likely due to a postzygotic mutation in the affected twin. Am. J. Med. Genet. 86:269–273, 1999. © 1999 Wiley-Liss, Inc.     

Spontaneously regressing brain lesions in Smith–Lemli–Opitz syndrome

Smith–Lemli–Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals’ clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.