Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management

4H leukodystrophy caused by a homozygous POLR3B mutation: Further delineation of the phenotype

4H leukodystrophy, also known as Pol III-related leukodystrophy, is a rare autosomal recessive neurodegenerative disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. It is caused by biallelic mutations in POLR3A, POL3RB, or POLR1C. So far, only two patients have been described with homozygosity for the common c.1568T>A (p.Val523Glu) POLR3B mutation, both of them showing a remarkably mild clinical course. Here, we report another patient with homozygosity for the same mutation, but with a more severe phenotype including ataxia, developmental delay, and intellectual disability. This information is of importance for clinicians to provide comprehensive counseling to patients with 4H leukodystrophy and their families

Expanding the phenotype of biallelic RNPC3 variants associated with growth hormone deficiency

Pathogenic variants in components of the minor spliceosome have been associated with several human diseases. Recently, it was reported that biallelic RNPC3 variants lead to severe isolated growth hormone deficiency and pituitary hypoplasia. The RNPC3 gene codes for the U11/U12-65K protein, a component of the minor spliceosome. The minor spliceosome plays a role in the splicing of minor (U12-type) introns, which are present in ~700–800 genes in humans and represent about 0.35% of all introns. Here, we report a second family with biallelic RNPC3 variants in three siblings with a growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. These cases further confirm the association between biallelic RNPC3 variants and severe postnatal growth retardation due to growth hormone deficiency. Furthermore, these cases show that the phenotype of this minor spliceosome-related disease might be broader than previously described

Fetal methotrexate syndrome: A systematic review of case reports

Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the ‘fetal methotrexate syndrome’. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The objective of this review is to delineate a consistent phenotype of the fetal methotrexate syndrome. We performed a systematic review that yielded 29 cases of (congenital) anomalies after in utero exposure to methotrexate and compared their malformation pattern to that of children and fetuses with congenital anomalies in general. Statistically significant higher proportions of microcephaly, craniosynostosis, tetralogy of Fallot, pulmonary valve atresia, limb reduction defects and syndactyly were found in the methotrexate group, indicating that these congenital anomalies are truly part of the fetal methotrexate syndrome. These results aid clinicians with diagnosing fetal methotrexate syndrome

Fetal methotrexate syndrome : A systematic review of case reports

Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the ‘fetal methotrexate syndrome’. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The objective of this review is to delineate a consistent phenotype of the fetal methotrexate syndrome. We performed a systematic review that yielded 29 cases of (congenital) anomalies after in utero exposure to methotrexate and compared their malformation pattern to that of children and fetuses with congenital anomalies in general. Statistically significant higher proportions of microcephaly, craniosynostosis, tetralogy of Fallot, pulmonary valve atresia, limb reduction defects and syndactyly were found in the methotrexate group, indicating that these congenital anomalies are truly part of the fetal methotrexate syndrome. These results aid clinicians with diagnosing fetal methotrexate syndrome

Fetal methotrexate syndrome: A systematic review of case reports

Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the ‘fetal methotrexate syndrome’. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The objective of this review is to delineate a consistent phenotype of the fetal methotrexate syndrome. We performed a systematic review that yielded 29 cases of (congenital) anomalies after in utero exposure to methotrexate and compared their malformation pattern to that of children and fetuses with congenital anomalies in general. Statistically significant higher proportions of microcephaly, craniosynostosis, tetralogy of Fallot, pulmonary valve atresia, limb reduction defects and syndactyly were found in the methotrexate group, indicating that these congenital anomalies are truly part of the fetal methotrexate syndrome. These results aid clinicians with diagnosing fetal methotrexate syndrome

<em>GMDS</em> Intragenic Deletions Associate with Congenital Heart Disease including Ebstein Anomaly

Ebstein anomaly is a rare heterogeneous congenital heart defect (CHD) with a largely unknown etiology. We present a 6-year-old girl with Ebstein anomaly, atrial septum defect, hypoplastic right ventricle, and persistent left superior vena cava who has a de novo intragenic ~403 kb deletion of the GDP-mannose 4,6-dehydratase (GMDS) gene. GMDS is located on chromosome 6p25.3 and encodes the rate limiting enzyme in GDP-fucose synthesis, which is used to fucosylate many proteins, including Notch1, which plays a critical role during mammalian cardiac development. The GMDS locus has sporadically been associated with Ebstein anomaly (large deletion) and tetralogy of Fallot (small deletion). Given its function and the association with CHD, we hypothesized that loss-of-function of, or alterations in, GMDS could play a role in the development of Ebstein anomaly. We collected a further 134 cases with Ebstein anomaly and screened them for genomic aberrations of the GMDS locus. No additional GMDS genomic aberrations were identified. In conclusion, we describe a de novo intragenic GMDS deletion associated with Ebstein anomaly. Together with previous reports, this second case suggests that GMDS deletions could be a rare cause for congenital heart disease, in particular Ebstein anomaly

Genetic diagnosis for rare diseases in the Dutch Caribbean: a qualitative study on the experiences and associated needs of parents

Research on the perspectives of patients and parents regarding genetic testing and its implications has been performed mostly in Europe, Canada, the United States, Australia and New Zealand, even though genetic testing is becoming increasingly available worldwide. We aimed to fill this knowledge gap by exploring the experiences and needs of parents in the Dutch Caribbean who received a genetic diagnosis for the rare disease of their child. We conducted 23 semi-structured interviews with 30 parents of children diagnosed with various rare genetic diseases in Aruba, Bonaire and Curaçao (ABC-islands). Two researchers independently analyzed the interviews using a thematic approach. Main themes identified were: (1) getting a genetic diagnosis, (2) coping, support and perceived social stigma, (3) living on a small island, and (4) needs regarding genetic services. Our results indicate that, despite reported limitations regarding the availability of healthcare and support services, receiving a genetic diagnosis for their child was valuable for most participants. While some of the participants’ experiences with and attitudes towards the genetic diagnosis of their child were similar to those reported in previous studies, we identified a number of aspects that are more specifically related to this Dutch Caribbean setting. These include coping through faith and religion, social stigma and being the only one on the island with a specific genetic disorder. The results of this study and the provided recommendations may be useful when developing genetic testing and counseling services in similar settings