Branchio-oto-renal syndrome: reduced penetrance and variable expressivity in four generations of a large kindred

The family on which this report is based is of interest because it contains individuals with the branchio-oto-renal (BOR) syndrome who have renal hypoplasia or malformations of the kidney or collecting system including duplication; only branchial and ear anomalies; and apparent nonpenetrance of the syndrome. This report provides evidence to support the hypothesis that in some families variable expressivity includes duplication of the urinary collecting system in individuals with other manifestations of the BOR syndrome as well as individuals with branchial and ear anomalies who have apparently normal kidneys.     

Molybdenum cofactor-deficient mice resemble the phenotype of human patients

Human molybdenum cofactor deficiency is a rare and devastating autosomal-recessive disease for which no therapy is known. The absence of active sulfite oxidase-a molybdenum cofactor-dependent enzyme-results in neonatal seizures and early childhood death. Most patients harbor mutations in the MOCS1 gene, whose murine homolog was disrupted by homologous recombination with a targeting vector. As in humans, heterozygous mice display no symptoms, but homozygous animals die between days 1 and 11 after birth. Biochemical analyis of these animals shows that molydopterin and active cofactor are undetectable. They do not possess any sulfite oxidase or xanthine dehydrogenase activity. No organ abnormalities were observed and the synaptic localization of inhibitory receptors, which was found to be disturbed in molybdenum cofactor deficient-mice with a Gephyrin mutation, appears normal. MOCS1(-/-) mice could be a suitable animal model for biochemical and/or genetic therapy approaches.     

Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype.

Myotonic dystrophy (DM) is associated with the expansion and instability of a trinucleotide (CTG) repeat in a sequence encoding a cAMP-dependent protein kinase. The normal copy number of 5-35 repeats is exceeded in DM patients, with the size of the expansion broadly correlating with the severity of symptoms experienced. In most families reported, the unstable DNA sequence has increased in size on transmission to affected offspring, thereby providing a molecular explanation for the phenomenon of anticipation in DM, i.e. an increase in the severity of symptoms associated with an earlier age at onset of the disease in successive generations of a family. Here we present the first reported case of a family where the transmission of the affected chromosome from father to son is accompanied by a reduction in the size of the triplet expansion, such that it falls within the normal range. As the son remains asymptomatic, this type of molecular event may provide an explanation for the incomplete penetrance of the disease phenotype reported for this disorder. The implications for genetic counselling of DM families and the mechanistic considerations of the trinucleotide instability are discussed.     

Brachy/ectrodactyly and absence or hypoplasia of the fibula: an autosomal dominant condition with low penetrance and variable expressivity

A complex dysostosis characterized by brachy- and/or ectrodactyly and fibular hypoplasia was found in two distantly related individuals. The proposita, aged 25 years, showed metacarpal and phalangeal hypoplasia on both hands, ectrodactyly on both feet, and nearly complete bilateral absence of the fibula. Only milder acromelic defects were detected in a second cousin. A similar pattern of skeletal involvement had been previously described in an unrelated Italian family. The peculiar segregation pattern can be explained by autosomal dominant inheritance with low penetrance and variable expressivity.     

Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor

The 2q37 deletion syndrome, also described in the literature as brachydactyly‐mental retardation syndrome (MIM 600430), is caused by deletion or haploinsufficiency of the HDAC4 gene, which encodes the histone deacetylase 4 protein. Although the most commonly described hallmark features of the 2q37 deletion syndrome include brachydactyly type E, developmental delay, obesity, autistic features, and craniofacial or skeletal dysmorphism, a literature review of 101 published cases plus two newly reported individuals indicates that there is a high degree of variability in the presence of some of the features that are considered the most characteristic of the syndrome: overweight and obesity (34%), cognitive‐behavioral issues (79%), dysmorphic craniofacial features (86%), and type E brachydactyly (48%). These features overlap with other neurodevelopmental conditions, including Smith‐Magenis syndrome (SMS), and may be incompletely penetrant or demonstrate variable expressivity, depending on the specific chromosomal anomaly. With the advent of fluorescence in situ hybridization (FISH), array‐based comparative genomic hybridization, and next‐generation DNA sequencing, more detailed molecular diagnoses are possible than in years past, enabling refined characterization of the genotype–phenotype correlation for subjects with 2q37 deletions. In addition, investigations into molecular and gene expression networks are expanding in neurodevelopmental conditions, and we surveyed HDAC4 downstream gene expression by quantitative real‐time polymerase chain reaction, further implicating HDAC4 in its role in the regulation of RAI1. Correlation of clinical data defining the impact on downstream gene expression and the potential clinical associations across neurodevelopment will improve our understanding of these complex conditions and potentially lead to common therapeutic approaches.     

Broadening the phenotype of LRRK1 mutations - Features of malignant osteopetrosis and optic nerve atrophy with intrafamilial variable expressivity

Osteosclerotic metaphyseal dysplasia is a rare disorder which features osteosclerosis involving long bones, vertebrae, ribs, clavicles and the iliac crests. Additional features which have variably been reported include developmental delay, short stature, hypotonia and seizures. The disease is caused by pathogenic variants in the LRRK1 gene, and inherited in an autosomal recessive manner. We report three siblings (ages 14 years, 11.5 years and 0.9 years), born to consanguineous parents of Arab-Muslim descent, harboring a homozygous pathogenic variant in the LRRK1 gene (Chr15:101068759 AGGGGCT>A, c.5965_5970del TGGGGC, p.Trp1989Gly1990del). The patients displayed variable degrees of skeletal dysplasia, with the oldest sibling most severely affected, and the youngest infant with minor skeletal involvement. Two of the siblings exhibited normal neurological development, while the youngest sibling exhibited global developmental delay. None of the siblings had seizures; however, two of them exhibited nystagmus. Optic nerve involvement has not previously been reported to be part of the clinical spectrum of this disease. The degree of optic nerve involvement did not correlate with the degree of skeletal involvement. This indicates both intra-familial variable expressivity along with a broadening of the spectrum of LRRK1-associated disease. These findings warrant reconsideration of therapeutic strategies, including the possibility of hematopoietic stem cell transplantation (HSCT) as is performed in cases of malignant and intermediate forms of osteopetrosis.     

Further delineation of dosage-sensitive K/L mediated Xq28 duplication syndrome includes incomplete penetrance

The low copy tandem repeat area at Xq28 is prone to recurrent copy number gains, including the K/L mediated duplications of 300 kb size (herein described as the K/L mediated Xq28 duplication syndrome). We describe five families, including nine males with K/L mediated Xq28 duplications, some with regions of greater copy number variation (CNV). We summarise findings in 25 affected males reported to date. Within the five families, males were variably affected by seizures, intellectual disability, and neurological features; however, one male with a familial K/L mediated Xq28 duplication has normal intelligence, suggesting that this CNV is not 100% penetrant. Including our five families, 13 carrier females have been identified, with nine presenting phenotypically normal. Three carrier females reported mild learning difficulties, and all of them had duplications containing regions with at least four copies. Delineation of the spectrum of K/L mediated Xq28 duplication syndrome highlights GDI1 as the most likely candidate gene contributing to the phenotype. For patients identified with CNVs in this region, high-resolution microarray is required to define copy number gains and provide families with accurate information.     

Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome

The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5′UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.     

A mouse model of AChR deficiency syndrome with a phenotype reflecting the human condition

The two subtypes of mammalian muscle nicotinic acetylcholine receptors (AChR) are generated by the substitution of the epsilon (adult) subunit for the gamma (fetal) subunit within the AChR pentamer. Null mutations of the adult AChR epsilon-subunit gene are the most common cause of the AChR deficiency syndrome. This is a disorder of neuromuscular transmission characterized by non-progressive fatigable muscle weakness present throughout life. In contrast with the human disorder, mice with AChR epsilon-subunit null mutations die between 10 and 14 weeks of age. We generated transgenic mice that constitutively express the human AChR gamma-subunit in an AChR epsilon-subunit 'knock-out' background. These mice, in which neuromuscular transmission is mediated by fetal AChR, live well into adult life but show striking similarities to human AChR deficiency syndrome. They display fatigable muscle weakness, reduced miniature endplate potentials and endplate potentials, reduced motor endplate AChR number and altered endplate morphology. Our results illustrate how species differences in the control of ion-channel gene expression may affect disease phenotype, demonstrate that expression of adult AChR subtype is not essential for long-term survival, and suggest that in patients with AChR deficiency syndrome, up-regulation of the gamma-subunit could be a beneficial therapeutic strategy.     

Limits of the general two-allele single locus model with incomplete penetrance

A graphical method is presented that allows an investigator to find the mathematical limits of the general one locus two allele genetic model for any trait whose population prevalence is known. It is seen that while the model is quite flexible in its ability to fit family data, there remains a large area where the model cannot be fitted. Specific sub-regions corresponding to particular hypotheses (e.g. underdominant v. intermediate v. overdominant) can be found, thereby limiting the area that needs to be searched by other more complicated techniques. Moreover, knowledge of where a set of observations lies can enable an investigator to frame and test specific subhypotheses.     

Asymmetric crying facies with microcephaly and mental retardation. An autosomal dominant syndrome with variable expressivity

An infant boy with asymmetric crying facies, microcephaly, developmental retardation and failure to thrive is reported. His two siblings died in the newborn period because of complex congenital heart defects. The mother and the maternal grandmother have asymmetric crying facies, microcephaly and normal intelligence. A maternal aunt has severe physical and mental retardation, facial asymmetry, microcephaly, and cleft palate. This family allows an expansion of the spectrum of malformations associated with asymmetric crying facies and suggests autosomal dominant inheritance with variable expressivity.     

Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype.

We have reviewed all known UK cases of Smith-Lemli-Opitz syndrome. Among 49 cases with proven 7-dehydrocholesterol reductase deficiency, half had been terminated or had died in infancy. The minimum incidence is 1 in 60,000. The frequent occurrence of hypospadias may account for 71% of recognised cases being male. Important common features which emerged include short thumbs, severe photosensitivity, aggressive behaviour, and atrioventricular septal defect. The typical facial appearance becomes less obvious with age and 20% of cases did not have 2/3 toe syndactyly. Biochemical measurements of serum 7-dehydrocholesterol did not correlate with clinical severity.     

The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome

This paper examines how COMT¹⁵⁸ genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer‐based test‐paradigms. Associations with COMT¹⁵⁸ genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMT^MET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMT^MET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT¹⁵⁸ genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants.     

Expansion and further delineation of the SETD5 phenotype leading to global developmental delay,variable dysmorphic features,and reduced penetrance

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.