Erratum: Discovery of a neuromuscular syndrome caused by biallelic variants in .

[This corrects the article DOI: 10.1016/j.xhgg.

Rare diseases: human genome research is coming home.

After a long and largely disappointing detour, Genome Research has reidentified Rare Diseases as a major opportunity for improving health care and a clue to understanding gene and genome function. In this Special Issue of on Rare Diseases, several invited Perspectives, numerous Case Reports, and this Editorial itself address recent breakthroughs as well as unsolved problems in this wide field. These range from exciting prospects for gap-free diagnostic whole-genome sequencing to persisting problems related to identifying and distinguishing pathogenic and benign variants; and from the good news that soon, the United Kingdom will no longer be the only country to have introduced whole-genome sequencing into health care to the sobering conclusion that in many countries the clinical infrastructure for bringing Genome Medicine to the patient is still lacking.

Discovery of a neuromuscular syndrome caused by biallelic variants in .

Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) is part of the four-part ASC-1 transcriptional cointegrator complex. This complex includes ASCC1 (associated with spinal muscular atrophy with congenital bone fractures 2), TRIP4 (associated with spinal muscular atrophy with congenital bone fractures 1), and ASCC2 (not yet associated with human disease.) encodes a DNA helicase responsible for generating single-stranded DNA as part of the DNA damage response.

POLRMT mutations impair mitochondrial transcription causing neurological disease.

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype.

A Novel Locus and Candidate Gene for Familial Developmental Dyslexia on Chromosome 4q.

Developmental dyslexia is a highly heritable specific reading and writing disability. To identify a possible new locus and candidate gene for this disability, we investigated a four-generation pedigree where transmission of dyslexia is consistent with an autosomal dominant inheritance pattern. We performed genome wide array-based SNP genotyping and parametric linkage analysis and sequencing analysis of protein-coding exons, exon-intron boundaries and conserved extragenic regions within the haplotype cosegregating with dyslexia in DNA from one affected and one unaffected family member.

Comprehensive genotype-phenotype correlation in AP-4 deficiency syndrome; Adding data from a large cohort of Iranian patients.

Mutations in adaptor protein complex-4 (AP-4) genes have first been identified in 2009, causing a phenotype termed as AP-4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype-phenotype correlation of the AP-4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease-causing variants in AP-4 complex subunits, using next-generation sequencing.

Whole genome sequencing identifies a duplicated region encompassing Xq13.2q13.3 in a large Iranian family with intellectual disability.

Background: The X chromosome has historically been one of the most thoroughly investigated chromosomes regarding intellectual disability (ID), whose etiology is attributed to many factors including copy number variations (CNVs). Duplications of the long arm of the X chromosome have been reported in patients with ID, short stature, facial anomalies, and in many cases hypoplastic genitalia and/or behavioral abnormalities.

Methods: Here, we report on a large Iranian family with X-linked ID caused by a duplication on the X chromosome identified by whole genome sequencing in combination with linkage analysis.

Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.

Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification.

Just Expect It: Compound Heterozygous Variants of POMT1 in a Consanguineous Family-The Role of Next Generation Sequencing in Neuromuscular Disorders.

Muscular dystrophy-dystroglycanopathies (MDDG) are a group of genetically heterogeneous autosomal recessive disorders characterized by hypoglycosylation of α-dystroglycan. Here, we report on two female patients from a consanguineous Lebanese family that presented in early infancy with generalized muscle hypotonia and primary microcephaly. Brain magnetic resonance imaging (MRI) showed different degrees of hypoplasia of the cerebellar vermis and hypoplasia of corpus callosum.

Homozygous variants in the gene SCAPER cause syndromic intellectual disability.

The S-Phase Cyclin A Associated Protein In The ER (SCAPER) gene is a ubiquitously expressed gene with unknown function in the brain. Recently, biallelic SCAPER variants were described in four patients from three families with retinitis pigmentosa (RP) and intellectual disability (ID). Here, we expand the spectrum of pathogenic variants in SCAPER and report on 10 further patients from four families with ID, RP, and additional dysmorphic features carrying homozygous variants in SCAPER.

Identification of disease-causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families.

Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next-generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families.

A mouse model for intellectual disability caused by mutations in the X-linked 2'‑O‑methyltransferase Ftsj1 gene.

Mutations in the X chromosomal tRNA 2'‑O‑methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143.

CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability.

The advent of high-throughput sequencing technologies has led to an exponential increase in the identification of novel disease-causing genes in highly heterogeneous diseases. A novel frameshift mutation in CNKSR1 gene was detected by Next-Generation Sequencing (NGS) in an Iranian family with syndromic autosomal recessive intellectual disability (ARID). CNKSR1 encodes a connector enhancer of kinase suppressor of Ras 1, which acts as a scaffold component for receptor tyrosine kinase in mitogen-activated protein kinase (MAPK) cascades.

Effect of inbreeding on intellectual disability revisited by trio sequencing.

In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near- and middle-east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown.

Biallelic missense variants in ZBTB11 can cause intellectual disability in humans.

Exploring genes and pathways underlying intellectual disability (ID) provides insight into brain development and function, clarifying the complex puzzle of how cognition develops. As part of ongoing systematic studies to identify candidate ID genes, linkage analysis and next-generation sequencing revealed Zinc Finger and BTB Domain Containing 11 (ZBTB11) as a novel candidate ID gene. ZBTB11 encodes a little-studied transcription regulator, and the two identified missense variants in this study are predicted to disrupt canonical Zn2+-binding residues of its C2H2 zinc finger domain, leading to possible altered DNA binding.

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations.

Genetics of intellectual disability in consanguineous families.

Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring.

Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.

Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here, we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.

Klüver-Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C).

Klüver-Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.

Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation.

Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent.

Exome Sequencing and Linkage Analysis Identified Novel Candidate Genes in Recessive Intellectual Disability Associated with Ataxia.

Background: Intellectual disability (ID) is a neuro-developmental disorder which causes considerable socio-economic problems. Some ID individuals are also affected by ataxia, and the condition includes different mutations affecting several genes.

Methods: We used whole exome sequencing (WES) in combination with homozygosity mapping (HM) to identify the genetic defects in five consanguineous families among our cohort study, with two affected children with ID and ataxia as major clinical symptoms.

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration.

AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder.

New evidence for the role of calpain 10 in autosomal recessive intellectual disability: identification of two novel nonsense variants by exome sequencing in Iranian families.

Background: Knowledge of the genes responsible for intellectual disability, particularly autosomal recessive forms, is rapidly expanding. Increasing numbers of the gene show great heterogeneity and supports the hypothesis that human genome may contain over 2000 causative genes with a critical role in brain development.

Methods: Since 2004, we have applied genome-wide SNP genotyping and next-generation sequencing in large consanguineous Iranian families with intellectual disability, to identify the genes harboring disease-causing mutations.