GC-MS as a tool for reliable non-invasive prenatal diagnosis of Smith-Lemli-Opitz syndrome but essential also for other cholesterolopathies verification

Rare multiple congenital malformations/developmental disorders are challenging in clinical diagnosis. The introductionof next-generation sequencing (NGS) has revolutionized this diagnostic by offering multigene panels or whole-exomesequencing. However, if there is no possibility to perform NGS or if we are facing prenatal ultrasound results, clinical diagnosticsis even more difficult. For a selected group of congenital metabolic disorders, resulting from defects in cholesterolbiosynthesis (called cholesterolopathies), application of gas chromatography-mass spectrometry (GS-MS) may provide ororientate diagnostics. The most common of these is Smith-Lemli-Opitz syndrome (SLOS), but in this publication, we alsowant to introduce other cholesterolopathies and draw attention to the possibility of non-invasive prenatal diagnosis of SLOS

Perinatal manifestations of congenital disorders of glycosylation—A clue to early diagnosis

N-glycosylation defects—isolated or mixed with other glycosylation defects—are the most frequent congenital disorders of glycosylation and present mostly in childhood, with a specific combination of non-specific phenotypic features. The diagnosis, however, is often delayed. The aim of this study is to describe the perinatal phenotype of congenital disorders of N-glycosylation. We present an analysis of perinatal symptoms in a group of 24 one-center Polish patients with N-glycosylation defects—isolated or mixed. The paper expands the perinatal phenotype of CDGs and shows that some distinctive combinations of symptoms present in the perinatal period should raise a suspicion of CDGs in a differential diagnosis

Clinical expression of Holt-Oram syndrome on the basis of own clinical experience considering prenatal diagnosis

Objectives: Holt-Oram syndrome manifests with defects of upper limbs, pectoral girdle and cardiovascular system. The aim of this paper was to present complex clinical picture of the syndrome and its variable expression on the example of the family diagnosed genetically on the neonatal ward, after proband’s prenatal examination. Maretial and methods: Nine family members were tested for TBX5 gene mutation. Results: Four of family members were diagnosed with Holt-Oram syndrome and five had correct genetic test results. The diagnosis allowed to identify a genetic risk family and enabled to provide them with genetic counselling. Conclusions: Diagnosis of Holt-Oram syndrome is possible as early as in prenatal period and it can be verified by genetic tests

Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.

Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10-12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype

Characteristics of Neuroimaging and Behavioural Phenotype in Polish Patients with PIGV-CDG—An Observational Study and Literature Review

Congenital disorders of glycosylation (CDGs) are a wide group of genetic diseases characterised by a severe clinical spectrum, consisting of developmental delays, dysmorphisms, and neurological deficits. Mutations in the PIGV gene lead to a disorder called hyperphosphatasia with impaired intellectual development syndrome 1 (HPMRS1), distinct from other CDGs in terms of hyperphosphatemia related to abnormal ALP activity and brachytelephalangy. This article discusses the phenotype of six Polish patients with HPMRS1 with a special focus on behavioural and imaging features, which were not addressed in 26 previously reported cases. The medical records of six patients aged 6 to 22 years were collected and analysed. In all cases, the same PIGV homozygotic mutation (c.1022C>A; p.Ala341Glu) was found, although the patients presented a diverse spectrum of neurological and developmental disorders, concerning in most cases the muscular tonus and general developmental delay. The most prevalent dysmorphic features included hypertelorism, high palate, and finger anomalies, whereas other characteristics present in all previously described cases, such as a short, broad nose and brachytelephalangy, were less frequently observed. Similarly to previous reports, the magnetic resonance (MR) and computed tomography (CT) head scans returned varied results, including physiological and pathological brain images in equal measure, the latter of which consisted of cortical atrophy, delayed myelination, hydrocephalus, and hypoplastic corpus callosum. Each patient exhibited symptoms characteristic of autism spectrum disorders, especially in terms of attention deficits, as well as controlling and expressing emotions. The most common type of sensory processing disorder was over-responsivity. Despite the low prevalence of HPMRS1, the patients reported in the literature presented a rather uniform phenotype, which does not correspond with the one found in each individual of the studied group. Behavioural disorders and sensory impairment require additional care and awareness considering the global developmental delay often observed in these patients

Spektrum objawów neurologicznych u 3-miesięcznego chłopca z zespołem Ehlersa i Danlosa (EDS) – opis przypadku

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders. The actual classification recognizes 13 subtypes of the syndrome. The classic type is the most common and in 90% of cases is caused by mutations in the COL5A1 and COL5A2 genes responsible for the synthesis of type V collagen. In other cases mutations in the COL1A1 gene encoding type I collagen are responsible for this disease. Classic EDS is characterized by skin hyperextensibility, poor wound healing and joint hypermobility. The clinical manifestation is dominated by symptoms from the musculoskeletal system, cardiovascular system, gastrointestinal tract and nervous system. Patients with Ehlers-Danlos syndrome also have a higher prevalence of obstructive sleep apnoea syndrome. The article presents the case of a 3-month-old boy with a classic type of the syndrome with tonic-clonic seizures, apnoea, fever of unknown cause, delayed psychomotor development with hypotonia, gastroesophageal reflux, fragility of blood vessels and easy bruising.Zespół Ehlersa i Danlosa to grupa chorób uwarunkowanych genetycznie, w których dochodzi do syntezy nieprawidłowych form kolagenu. Wyróżniamy 13 postaci klinicznych zespołu, z których postać klasyczna należy do najczęstszych i w 90% spowodowana jest mutacjami w genach COL5A1 i COL5A2 odpowiedzialnych za syntezę prokolagenu typu V. W pozostałych przypadkach odpowiedzialną za wystąpienie tej choroby jest mutacja w genie COL1A1 kodującym prokolagen typu I. Postać klasyczną zespołu Ehlersa i Danlosa charakteryzuje nadmierna ruchomość stawów i rozciągliwość skóry oraz słabe gojenie się ran. W obrazie klinicznym dominują objawy ze strony układu mięśniowo-szkieletowego, sercowo-naczyniowego, przewodu pokarmowego oraz układu nerwowego. U pacjentów z zespołem Ehlersa i Danlosa stwierdzono również zwiększoną częstość występowania zespołu obturacyjnego bezdechu. Artykuł prezentuje przypadek 3-miesięcznego chłopca z klasyczną postać zespołu, u którego obserwowano napady toniczno- kloniczne, bezdechy ze spadkami saturacji, gorączki o nieustalonej etiologii, opóźnienie rozwoju ruchowego z uogólnioną wiotkością, refluks żołądkowo-przełykowy, kruchość naczyń krwionośnych i skłonność do siniaczeń