Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) is a rare, autosomal-dominant or -recessive disorder characterized primarily by aplasia cutis congenita and terminal transverse limb defects. Recently, we demonstrated that homozygous mutations in DOCK6 cause an autosomal-recessive form of AOS. In this study, we sought to determine the contribution of DOCK6 mutations to the etiology of AOS in several consanguineous families. In two of the five families studied, we identified two homozygous truncating mutations (a splice-site mutation and a frameshift duplication). DOCK6 sequencing revealed no mutation in the remaining three families, consistent with their autozygosity mapping and linkage-analysis results, which revealed a single candidate locus in 3p14.1 on three different haplotype backgrounds in the three families. Indeed, exome sequencing in one family revealed one missense mutation in EOGT (C3orf64), and subsequent targeted sequencing of this gene revealed a homozygous missense mutation and a homozygous frameshift deletion mutation in the other two families. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-GlcNAc to serine and threonine residues) of a subset of extracellular EGF-domain-containing proteins. It has a documented role in epithelial-cell-matrix interactions in Drosophila, in which deficiency of its ortholog causes wing blistering. Our findings highlight a developmental role of O-GlcNAcylation in humans and expand the genetic heterogeneity of autosomal-recessive AOS.

Limb malformations with associated congenital constriction rings in two unrelated Egyptian males, one with a disorganization-like spectrum and the other with a probable distinct type of septo-optic dysplasia.

In this report, we describe two unrelated Egyptian male infants with limb malformations and constriction rings. The first case is developing normally but has severe limb anomalies, congenital constriction rings, scoliosis because of vertebral anomalies, a left accessory nipple, a small tumor-like swelling on his lower back with tiny skin tubular appendages, a hypoplastic scrotum, and an anchored penis. The second case is developmentally delayed with limb malformations, congenital constriction rings, a lumbar myelomeningeocele, hemangioma, and tiny tubular skin appendages on the back. The patient also had bilateral optic atrophy. The constellation of features in our patients cannot be fully explained by the amniotic disruption complex. The first patient may represent an additional case of the human homolog of the mouse disorganization mutant. The presence of bilateral optic atrophy in the second case, although without an absent septum pellucidum nor other brain anomalies resembles the infrequently reported disorder of septo-optic dysplasia with limb anomalies. Both cases were sporadic and could be caused by a new dominant mutation because of the high paternal age of case 1 and the history of paternal occupational exposure to heat for both fathers. We draw attention to the phenotypic overlap between the disorganization-like syndrome and septo-optic dysplasia with limb anomalies.

Dyggve-Melchior-Clausen syndrome: clinical, genetic, and radiological study of 15 Egyptian patients from nine unrelated families.

INTRODUCTION: Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive type of skeletal dysplasia. It is characterized by the association of progressive spondyloepimetaphyseal dysplasia (SEMD), microcephaly, mental retardation (MR), and coarse facies. The radiographic appearance of generalized platyspondyly with double-humped end plates and the lace-like appearance of iliac crests are pathognomonic and distinctive of DMC syndrome. The disorder results from mutations in the DYM gene mapped in the 18q12-12.1 chromosomal region. MATERIALS AND METHODS: In this report, we studied 15 Egyptian cases with DMC syndrome from nine unrelated families. We aimed to emphasize the characteristic clinical and radiological features in order to differentiate the condition from other SEMDs and mucopolysaccharidosis (MPS). Patients were subjected to detailed history taking, three-generation family pedigree analysis, complete physical examination, anthropometric measurements, quantitative estimation, and two-dimensional electrophoresis of glycosaminoglycans in the urine and measurement of α-l-iduronidase and galactose-6-sulfatase enzyme activities to exclude Hurler and Morquio diseases (MPS type I and MPS type IVA), respectively. Other investigations were carried out whenever indicated. All patients were the offspring of consanguineous apparently normal parents. Positive family history and similarly affected sibs were noted, confirming the autosomal recessive inheritance pattern of the syndrome. Short stature, microcephaly, variable degree of MR, and coarse facies were constant features. The frequency of characteristic orthopedic and radiological findings was reported. Orthopedic surgical intervention was carried out for two patients. CONCLUSIONS: The study concluded that DMC syndrome may be more frequent in Egypt than previously thought, especially due to misdiagnosis. Characteristic facial dysmorphism, body habitus, and pathognomonic radiological signs suggest the diagnosis and differentiate it from other types of SEMDs and MPS for proper genetic counseling and management.

Long interspersed nuclear element-1 (LINE1)-mediated deletion of EVC, EVC2, C4orf6, and STK32B in Ellis-van Creveld syndrome with borderline intelligence.

Previous work has shown Ellis-van Creveld (EvC) patients with mutations either in both alleles of EVC or in both alleles of EVC2. We now report affected individuals with the two genes inactivated on each allele. In a consanguineous pedigree diagnosed with EvC and borderline intelligence, we detected a 520-kb homozygous deletion comprising EVC, EVC2, C4orf6, and STK32B, caused by recombination between long interspersed nuclear element-1 (LINE-1 or L1) elements. Patients homozygous for the deletion are deficient in EVC and EVC2 and have no increase in the severity of the EvC typical features. Similarly deletion carriers demonstrate absence of digenic inheritance in EvC. Further, the phenotype of these patients suggests that the EVC-STK32B deletion also leads to mild mental retardation and reveals that loss of the novel genes C4orf6 and STK32B causes at most mild mental deficit. In an EvC compound heterozygote of different ethnic origin we identified the same LINE-to-LINE rearrangement due to a different recombination event. These findings highlight the importance of L1 repetitive sequences in human genome architecture and disease.

Adams-Oliver syndrome: further evidence of an autosomal recessive variant.

Adams-Oliver syndrome is characterized by aplasia cutis congenita and variable degrees of terminal transverse limb defects. Other associated anomalies were described in the syndrome. Most described cases follow an autosomal dominant pattern of inheritance. Sporadic and autosomal recessive cases, however, were reported. In this study, we report on three Egyptian patients with Adams-Oliver syndrome from three different families. The parents were normal and consanguineous in all three families. There was history of similarly affected sibs for two cases. These findings denote autosomal recessive inheritance. The reported cases had typical skull and limb anomalies with cutis marmorata telangiectatica congenita. We observed additional rare manifestations in the form of microcephaly, psychomotor retardation, epilepsy, eye anomalies and atrophic skin lesions. MRI of the brain in one of the studied cases revealed retrocerebellar cyst and mild asymmetrical cerebellar hypoplasia, which to our knowledge, were not previously reported in Adams-Oliver syndrome. The results of this study provide further evidence of clinical and genetic heterogeneity and support the presence of autosomal recessive variant of Adams-Oliver syndrome.

3-M syndrome: a report of three Egyptian cases with review of the literature.

The 3-M syndrome is a rare autosomal recessive disorder. It is characterized by prenatal and postnatal growth retardation associated with characteristic features. In this study, we report on three patients from two unrelated families, including two male sibs, with the characteristic features and radiological findings of the 3-M syndrome. The main features in our cases were low birth weight, short stature, malar hypoplasia, anteverted nostrils with a fleshy nasal tip, long philtrum, pointed full chin, short broad neck, broad chest with transverse grooves of anterior thorax and hyperlordosis. An orodental examination revealed characteristic findings, some of which were not reported before. Prominent premaxilla, hypoplastic maxilla, thick patulous lips, high-arched palate, median fissured tongue, delayed eruption of teeth with enamel hypocalcification and malocclusion were present in our three studied cases. Radiographic studies showed slender long bones and ribs, a narrow pelvis and foreshortened vertebral bodies. Our reported cases are the offspring of healthy consanguineous parents, confirming the autosomal recessive pattern of inheritance in the syndrome. Cases were reported from different countries all over the world. To our knowledge, these are the first reported Egyptian patients with this rare disorder. This syndrome may be underreported because of the phenotypic overlap with other low birth dwarfism syndromes. Recent identification of a gene mutated in some cases of 3-M syndrome will aid diagnosis.