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Background: Syndactyly is a clinical feature of split-hand foot malformation (SHFM), ectodermal-dysplasia-syndactyly (EDSS1) and Cenani-Lenz syndactyly syndromes (CLSS). In EDSS1, only cutaneous syndactyly is observed, with sparse hair, abnormal nails and dentition. In SHFM, bony syndactyly may vary from hypoplasia of one phalanx to aplasia of central digits, extending to complete fusion of all fingers and toes in CLSS. Several genes have been assigned to these syndromes. Performing a single step molecular diagnostics becomes a challenge when a phenotype has overlaps with several syndromes or when some of the clinical features are not fully expressed in patients., Methods: Whole exome sequencing (WES) analysis on one sample derived from a consanguineous family was performed. A causative variant in WES data was prioritized via standard bioinformatics tools. The selected variant was Sanger sequenced in all the available family members for autosomal recessive segregation., Results: A novel missense variant (c.1151A>G; p.Tyr384Cys) was identified in the LRP4 gene. Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were heterozygous for this variant. The variant is neither reported in 1000 human genomes, nor in 60 706 exomes databases, and is predicted as "pathogenic" by SIFT, Polyphen-2 and MutationTaster software., Conclusions: The present study broadens the pathogenic spectrum of the LRP4 gene in syndactyly syndromes. WES is a powerful tool for genetic analysis in research and can be readily used as a first-line diagnostic test in syndactyly and related phenotypes., (© 2019 John Wiley & Sons, Ltd.)

Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities.

Perrault syndrome (PRLTS) is a clinically and genetically heterogeneous disorder. Both male and female patients suffer from sensory neuronal hearing loss in early childhood, and female patients are characterized by premature ovarian failure and infertility after puberty. Clinical diagnosis may not be possible in early life, because key features of PRLTS, for example infertility and premature ovarian failure, do not appear before puberty. Limb spasticity, muscle weakness, and intellectual disability have also been observed in PRLTS patients. Mutations in five genes, HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. We discovered a consanguineous Saudi family with the PRLTS3 phenotype showing an autosomal recessive mode of inheritance. The patients had developed profound hearing loss, brain atrophy, and lower limb spasticity in early childhood. For molecular diagnosis, we complimented genome-wide homozygosity mapping with whole exome sequencing analyses and identified a novel homozygous mutation in exon 6 of CLPP at chromosome 19p13.3. To our knowledge, early onset with regression is a unique feature of these PRLTS patients that has not been reported so far. This study broadens the clinical spectrum of PRLTS3., (Copyright © 2015 Elsevier B.V. All rights reserved.)