[The 46,XX male; a chromosomal form of a disorder of sex development]. / De 46,XX-man.

BACKGROUND: A disorder of sex development (abbreviated DSD) is defined as a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. DSD is caused by a disruption of foetal sexual development, which is largely influenced by various genetic and hormonal factors. The SRY gene, located on the Y chromosome, plays a key role in sexual development. CASE DESCRIPTION: A 32-year-old male was found to be infertile because of azoospermia. His habitus was that of a male. Hormonal analysis revealed hypergonadotropic hypogonadism. Karyotyping and fluorescence in situ hybridisation (FISH) revealed a 46,XXSRY+ pattern due to an unbalanced X;Y translocation in the presence of SRY on an X chromosome, this is classified as a chromosomal form of DSD. CONCLUSION: Male infertility can be caused by DSD, even if a male habitus makes this seem unlikely at first.

Truncating de novo mutations in the Krüppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms.

BACKGROUND: Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder. METHODS: Routine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies. RESULTS: In a cohort of 2172 patient-parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012-2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5.42 × 10-3). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. CONCLUSIONS: We propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent-offspring trio approach for identifying novel genes involved in rare human diseases.

An update on ECARUCA, the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations.

The European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA, www.ecaruca.net) is an online database initiated in 2003 that collects and provides detailed, curated clinical and molecular information on rare unbalanced chromosome aberrations. ECARUCA now contains over 4800 cases with a total of more than 6600 genetic aberrations and has over 3000 account holders worldwide. Recently, the ECARUCA web site was renewed, including the presentation of interesting case reports in collaboration with the European Journal of Medical Genetics. This article gives an overview of the current status and future plans of the online ECARUCA database.

Question mark ears and post-auricular tags.

Questions mark ears are an easily recognisable but uncommon malformation of the external ear. They can be found as an isolated malformation and are a pathognomonic sign of the auriculo-condylar syndrome. An additional unique sign in this syndrome may be present in the form of post-auricular tags. Such malformations should prompt further investigation for other signs of the auriculo-condylar syndrome.

Familial CHARGE syndrome and the CHD7 gene: a recurrent missense mutation, intrafamilial recurrence and variability.

CHARGE syndrome is an autosomal dominant condition that is caused by mutations in the CHD7 gene. Few familial cases of this syndrome have been reported and these were characterized by a wide clinical variability. We here report on five CHD7 mutation positive families and comment on their clinical features. We observed somatic and germline mosaicism as well as parent-to-child transmission of non-mosaic CHD7 mutations as causes of familial CHARGE syndrome. In one family with two affected sibs a somatic mutation was identified in lymphocytes of a clinically unaffected parent (2520G > A in exon 8). This is the second report of somatic CHD7 mosaicism in an unaffected parent. In two further families with affected siblings, we could not detect the mutation in parental lymphocytes suggesting germline mosaicism. The previously reported clinical variability was strikingly present in all five families. We find that alterations in CHD7 can result in a very mild phenotype, characterized by only a few minor symptoms of the CHARGE syndrome clinical spectrum. Such a mild phenotype was present in two families that shared the same 6322G > A missense mutation. These two families showed parent-to-child transmission. Phenotypically milder forms of CHARGE syndrome have a higher risk of transmission to multiple family members.

Two related Dutch families with a clinically variable presentation of cardioskeletal myopathy caused by a novel S13F mutation in the desmin gene.

Desmin-related myopathy is characterised by skeletal muscle weakness often combined with cardiac involvement. Mutations in the desmin gene have been described as a cause of desmin-related myopathy (OMIM 601419). We report here on two distantly related Dutch families with autosomal dominant inheritance of desmin-related myopathy affecting 15 family members. A highly heterogeneous clinical picture is apparent, varying from isolated dilated cardiomyopathy to a more generalised skeletal myopathy and mild respiratory problems. Morphological analysis of muscle biopsies revealed intracytoplasmic desmin aggregates (desmin and p62 staining). In both families we identified an identical novel pathogenic heterozygous missense mutation, S13F, in the 'head' domain of the desmin gene which cosegregates with the disease phenotype. This is the 5th reported missense mutation located at the 'head' domain of the desmin gene and the first reported Dutch family with desmin-related myopathy. This article illustrates the importance of analysing the desmin gene in patients with (familial) cardiac conduction disease, dilated cardiomyopathy and/or a progressive skeletal myopathy resembling limb-girdle muscular dystrophy.

CHARGE syndrome: relations between behavioral characteristics and medical conditions.

The behaviors and medical problems in 27 persons with CHARGE syndrome were studied, because it was hypothesized that their behavior might be partly dependent on the heterogeneous medical status. With the exception of more tics, cardiac surgery was associated with positive behaviors: less withdrawn behavior, better mood, and a more easy temperament. Tube feeding was also related to positive behavior, since participants with a history of tube feeding showed less intense behavior. Cerebral deficits were associated with three problem behaviors: more intense and withdrawn behavior and a worse mood. Deaf-blindness was associated with developmental delays in expressive and overall communication level, and recurrent middle ear infections correlated with delays in written language. Of all medical conditions, only the presence or absence of heart defects and cardiac surgery could differentiate between the participants with regard to the number of behavioral problems. Participants with heart surgery especially, had less behavior problems. The number of operations and hospitalizations was not associated with behavior, but the total length of the hospitalizations was. Long hospital stays were associated with less problem behavior, especially internalizing behaviors. Cerebral and heart problems did not result in longer hospital stays, whereas esophageal reflux did. Age effects were reflected in older participants, who showed more internalizing problems. Heart surgery and hospitalization may be protective factors, but the protection might not be the actual surgery or hospital stay, as there may be other variables that are the actual cause, such as reduced vitality or altered parent child interactions after heart surgery. The study could not confirm a significant association between medical conditions and autism found in previous studies.

Chromosome 3 translocations and familial renal cell cancer.

Renal cell carcinomas (RCCs) occur in both sporadic and familial forms. In a subset of families the occurrence of RCCs co-segregates with the presence of constitutional chromosome 3 translocations. Previously, such co-segregation phenomena have been widely employed to identify candidate genes in various hereditary (cancer) syndromes. Here we survey the translocation 3-positive RCC families that have been reported to date and the subsequent identification of its respective candidate genes using positional cloning strategies. Based on allele segregation, loss of heterozygosity and mutation analyses of the tumors, a multi-step model for familial RCC development has been generated. This model is relevant for (i) understanding familial tumorigenesis and (ii) rational patient management. In addition, a high throughput microarray-based strategy is presented that will enable the rapid identification of novel positional candidate genes via a single step procedure. The functional consequences of the (fusion) genes that have been identified so far, the multi-step model and its consequences for clinical diagnosis, the identification of persons at risk and genetic counseling in RCC families are discussed.

Mutations in a new member of the chromodomain gene family cause CHARGE syndrome.

CHARGE syndrome is a common cause of congenital anomalies affecting several tissues in a nonrandom fashion. We report a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 identified by array comparative genomic hybridization in two individuals with CHARGE syndrome. Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals.

High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization.

Telomeric chromosome rearrangements may cause mental retardation, congenital anomalies, and miscarriages. Automated detection of subtle deletions or duplications involving telomeres is essential for high-throughput diagnosis, but impossible when conventional cytogenetic methods are used. Array-based comparative genomic hybridization (CGH) allows high-resolution screening of copy number abnormalities by hybridizing differentially labeled test and reference genomes to arrays of robotically spotted clones. To assess the applicability of this technique in the diagnosis of (sub)telomeric imbalances, we here describe a blinded study, in which DNA from 20 patients with known cytogenetic abnormalities involving one or more telomeres was hybridized to an array containing a validated set of human-chromosome-specific (sub)telomere probes. Single-copy-number gains and losses were accurately detected on these arrays, and an excellent concordance between the original cytogenetic diagnosis and the array-based CGH diagnosis was obtained by use of a single hybridization. In addition to the previously identified cytogenetic changes, array-based CGH revealed additional telomere rearrangements in 3 of the 20 patients studied. The robustness and simplicity of this array-based telomere copy-number screening make it highly suited for introduction into the clinic as a rapid and sensitive automated diagnostic procedure.