Contributing to the early detection of Rett syndrome: The potential role of auditory Gestalt perception

► First study into the potential role of auditory Gestalt perception for an early detection of RTT. ► The study adds to our understanding of pre-regressional abnormalities in RTT. ► Verbal development in RTT is atypical from the first vocalizations onwards. ► Early atypical verbal behavior is a window to the developing nervous system. ► The study contributes to the early detection of RTT for early intervention

Heterozygous <i>De Novo</i> and Inherited Mutations in the Smooth Muscle Actin (<i>ACTG2</i>) Gene Underlie Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

<div><p>Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous <i>ACTG2</i> missense variants in 15 unrelated subjects, ten being apparent <i>de novo</i> mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent <i>de novo</i> mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that <i>ACTG2</i> is responsible for a spectrum of smooth muscle disease. <i>ACTG2</i> encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.</p></div

Response to name and its value for the early detection of developmental disorders: Insights from autism spectrum disorder, Rett syndrome, and fragile X syndrome. A perspectives paper

Background: Responding to one's own name (RtN) has been reported as atypical in children with developmental disorders, yet comparative studies on RtN across syndromes are rare. Aims: We aim to (a) overview the literature on RtN in different developmental disorders during the first 24 months of life, and (b) report comparative data on RtN across syndromes. Methods and procedures: In Part 1, a literature search, focusing on RtN in children during the first 24 months of life with developmental disorders, identified 23 relevant studies. In Part 2, RtN was assessed utilizing retrospective video analysis for infants later diagnosed with ASD, RTT, or FXS, and typically developing peers. Outcomes and results: Given a variety of methodologies and instruments applied to assess RtN, 21/23 studies identified RtN as atypical in infants with a developmental disorder. We observed four different developmental trajectories of RtN in ASD, RTT, PSV, and FXS from 9 to 24 months of age. Between-group differences became more distinctive with age. Conclusions and implications: RtN may be a potential parameter of interest in a comprehensive early detection model characterising age-specific neurofunctional biomarkers associated with specific disorders, and contribute to early identification

CpG dinucleotides within arginine codons are targets of <i>de novo</i> events in MMIHS.

<p>A.) The coding exons are shown with translation for the <i>ACTG2</i> gene. CpG dinucleotides are highlighted in red. Arginine residues in the protein are highlighted in green, and the mutations associated with <i>ACTG2</i> smooth muscle disease are aligned above the sequence. B.) The frequency of codon usage per 1000 codons for 6 arginine codons is shown. The human genome as a whole (bottom bar) is compared to all human actin genes including <i>ACTG2</i>.</p

<i>ACTG2</i> mutations affect conserved residues that are also targets for Mendelian disease.

<p>A.) Depiction of the mutations on the exons of the gene. Introns are not shown to scale. The mutations associated with MMIHS and intestinal pseudo-obstruction (orange) and those associated with intestinal pseudo-obstruction (green), including the previously reported mutation in one Finnish family are shown. A nonsense allele at position R63 was identified in our exome database associated with no clinical phenotype. The black, red, and blue lines under specific mutations highlight areas of multi-sequence alignment in boxes of corresponding colors in B. B.) Comparison of the mutations in MMIHS/intestinal pseudo-obstruction with disease causing mutations in other actin genes.</p

Characteristics of the <i>ACTG2</i> mutations in the MMIHS cohort.

a<p>Deduced cDNA change in transcript NM_001615 unless otherwise indicated.</p>b<p>Transcript Uc010fex.1.</p>c<p>Deduced amino acid substitution.</p>d<p>Presence of the observed mutation in other exomes from the Baylor Center for Mendelian Genomics cohort.</p

Clinical characteristics of the patients with MMIHS due to <i>ACTG2 de novo</i> mutations.

<p>+ Feature present, − Feature absent,</p><p>*M- Metaclopramide, Cis- Cisapride, E-Erythromycin, (+) responsive, (−) non-responsive.</p

Clinical features and inheritance of <i>ACTG2</i> mutations in <i>de novo</i> and familial cases.

<p>Family pedigrees with clinical features correlated with the severity of smooth muscle dysfunction are shown. The most severe features of TPN dependence and megacystic bladder noted as dark squares within the upper quarters. The diagnosis of MMIHS (orange) was made in all but one subject with <i>de novo ACTG2</i> mutations. One subject (Fam 12-1) was diagnosed with gastrointestinal hollow visceral myopathy but had megacystis prenatally. Three families exhibiting dominant inheritance patterns are depicted below. One subject (Fam 13-1) suffered from a megacystic bladder but had later onset functional GI pseudo-obstruction. Another family (Fam19) is shown with two affected siblings with functional GI obstruction. Both carry a nonsynonymous mutation in alternate exon 4 of a predicted short <i>ACTG2</i> isoform (Uc010fex.1 indicated by *). Another family exhibited more extensive dominant inheritance (Fam34) consistent with familial visceral myopathy. Multiple paternal relatives suffer from episodes of gastrointestinal obstruction, constipation, gastrointestinal dysmotility, and bladder dysmotility segregating with the same mutation.</p

Exome analysis summary for six probands with MMIHS due to <i>ACTG2</i> mutations.

<p>Exome analysis summary for six probands with MMIHS due to <i>ACTG2</i> mutations.</p