Mesoaxial synostotic syndactyly, Malik-Percin type (MSSD) (syndactyly type IX) is a rare autosomal-recessive nonsyndromic digit anomaly with only two affected families reported so far. We previously showed that the trait is genetically distinct from other syndactyly types, and through autozygosity mapping we had identified a locus on chromosome 17p13.3 for this unique limb malformation. Here, we extend the number of independent pedigrees from various geographic regions segregating MSSD to a total of six. We demonstrate that three neighboring missense mutations affecting the highly conserved DNA-binding region of the basic helix-loop-helix A9 transcription factor (BHLHA9) are associated with this phenotype. Recombinant BHLHA9 generated by transient gene expression is shown to be located in the cytoplasm and the cell nucleus. Transcription factors 3, 4, and 12, members of the E protein (class I) family of helix-loop-helix transcription factors, are highlighted in yeast two-hybrid analysis as potential dimerization partners for BHLHA9. In the presence of BHLHA9, the potential of these three proteins to activate expression of an E-box-regulated target gene is reduced considerably. BHLHA9 harboring one of the three substitutions detected in MSSD-affected individuals eliminates entirely the transcription activation by these class I bHLH proteins. We conclude that by dimerizing with other bHLH protein monomers, BHLHA9 could fine tune the expression of regulatory factors governing determination of central limb mesenchyme cells, a function made impossible by altering critical amino acids in the DNA binding domain. These findings identify BHLHA9 as an essential player in the regulatory network governing limb morphogenesis in humans.

We report on nine members of a consanguineous Pakistani family with primary presentation of intellectual disability, developmental delay, limb and gait ataxia, behavioral and speech problems, and tremor. By linkage mapping and exome sequencing we identified novel homozygous splicing variant c.6375-1G>C in SPTBN2. To date, only two other SPTBN2 mutations with recessive pattern of inheritance causing SCAR14 (spinocerebellar ataxia, autosomal recessive 14) that manifest with developmental ataxia and cognitive impairment, or cerebellar ataxia, mental retardation, and pyramidal signs have been reported. The mutation we identified is predicted to lead to the deletion of just the pleckstrin homology domain; thus, the earlier onset and more progressive nature of the disease in the presented family, as compared to earlier reports, were unexpected. No other mutation that could possibly explain the features that were unusual for SCAR14-arched palate, limb hypotonia, climacophobia, and behavioral problems-was identified. The disease was more severe in males than females. Our findings expand the recessive SPTBN2 mutation phenotype. We also review SPTBN2 mutation phenotypes. The gene encodes beta-III spectrin, which forms tetramers with alpha-II spectrin. The manifestations of this third recessive mutation suggest that for recessive mutations either no mutant protein is synthesized because the transcript is subject to nonsense-mediated decay or the mutant protein does not bind membrane proteins and, thus, does not exert a negative effect in heterozygotes, whereas the dominant mutations causing SCA5 form defective tetramers that compete with the native tetramers in binding membrane proteins, but are unable to anchor them.

encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. The variant in , encoding a transcription factor that localises to the primary cilium and nucleus and is a mediator of the sonic hedgehog pathway, possibly exacerbates disease severity when in the homozygous state.

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Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3 C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3 C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3 C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3 C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.

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Background Pakistan faces high incidence of congenital anomalies (CA) and hereditary anomalies due to various factors, including a high rate of consanguinity, early marriages, and predominance of extended families. There is a paucity of epidemiological studies that could provide a baseline for management strategies for these anomalies. Objectives We aimed to elucidate the pattern, as well as the clinical and genetic aspects, of CA prevalence among the general population in Sialkot District of Pakistan. Methods In a cross-sectional sampling design, subjects and families with a certain type of CA were recruited from hospitals and medical centers in Sialkot District. Subjects were also selected from various towns and remote villages by visiting public places. Phenotypic and descriptive data were obtained, pedigrees were constructed, and parental and demographic attributes were recorded. Results A total of 241 independent subjects and/or families with CA were recruited. The malformations were classified into five major and 56 minor categories. Limb defects had the highest representation (n = 113; proportion = 0.469; 95% confidence interval (CI) = 0.406–0.532), followed by neurological anomalies (n = 76; proportion = 0.315; 95% CI = 0.257–0.374). Among the limb defects, polydactyly and talipes were most prevalent while, among neurological disorders, intellectual disability and cerebral palsy were more frequent. In this cohort, sporadic occurrence was customary compared to the familial presentation (n = 144 vs 97). Analyses of various attributes, such as gender differences, parental consanguinity, and paternal ages, as well as pedigree analyses, revealed marked heterogeneity among the major and minor categories of CA. Conclusion The pattern of anomalies witnessed in this cohort and a high occurrence of sporadic cases point to a substantial role of nongenetic etiological factors, which could be minimized by strengthening the health-care system.