A novel non-recurrent CNV deletion involving TBX4 and leaving TBX2 intact causes congenital alveolar dysplasia.

Congenital alveolar dysplasia (CAD) belongs to rare lethal lung developmental disorders (LLDDs) in neonates, manifesting with acute respiratory failure and pulmonary arterial hypertension refractory to treatment. The majority of CAD cases have been associated with copy-number variant (CNV) deletions at 17q23.1q23.2 or 5p12. Most CNV deletions at 17q23.1q23.2 were recurrent and encompassed two closely located genes, TBX4 and TBX2. In a few CAD cases, intragenic frameshifting deletions or single-nucleotide variants (SNVs) involved TBX4 but not TBX2. Here, we describe a male neonate who died at 27 days of life from acute respiratory failure caused by lung growth arrest along the spectrum of CAD confirmed by histopathological assessment. Trio-based genome sequencing revealed in the proband a novel non-recurrent ~1.07 Mb heterozygous CNV deletion at 17q23.2, encompassing TBX4 that arose de novo on the paternal chromosome. This is the first report of a larger-sized CNV deletion in a CAD patient involving TBX4 and leaving TBX2 intact. Our results, together with previous reports, indicate that perturbations of TBX4, rather than TBX2, cause severe lung phenotypes in humans.

Clinical heterogeneity of polish patients with KAT6B-related disorder.

BACKGROUND: Say-Barber-Biesecker-Young-Simpson (SBBYSS) variant of Ohdo syndrome is a rare, autosomal dominant and clinically heterogenous disorder, caused by pathogenic variants in the KAT6B gene located on chromosome 10q22.2. KAT6B encodes a highly conserved histone acetyltransferase belonging to the MYST family. Currently, diseases caused by pathogenic variants in KAT6B (KAT6B-related disorders) comprise two allelic entities: SBBYSS variant of Ohdo syndrome and genitopatellar syndrome (GPS). Increase in the number of cases with overlapping GPS/SBBYSS phenotype which makes it necessary to redefine this group of phenotypes as KAT6B-related disorders or KAT6B spectrum disorders. Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes. This syndrome also typically involves skeletal problems including patellar hypoplasia/agenesis. METHODS: Here we report six SBBYS syndrome patients with the same dysmorphic features but a different course of the disease. One known and five novel KATB6 pathogenic variants were identified by molecular diagnostics using Next Generation Sequencing (NGS). RESULTS: We present a detailed phenotypic analysis of six individuals with KAT6B-related disorders, in whom a heterozygous pathogenic variant in KAT6B gene was found. In all of our patients facial dysmorphism as well as developmental and speech delay were present. Additionally, all but one patients presented with hypotonia, ocular abnormalities and long thumbs. Most of our probands showed blepharophimosis and skeletal (mainly knee) defects. Contrary to previously reported severe patellar defects (hypoplasia/agenesis) anomalies presented by our patients were less severe (dysplasia, habitual dislocation, subluxation) referring to KAT6B-related disorders. CONCLUSION: While most of the anomalies found in our patients comply with SBBYSS criteria, phenotypic differences in our probands support a broader spectrum of the disease phenotype. To establish the range of this spectrum, a detailed analysis of clinical variability among patients with SBBYSS requires further investigation.

Epigenetic Findings in Twins with Esophageal Atresia.

Esophageal atresia (EA) is the most common malformation of the upper gastrointestinal tract. The estimated incidence of EA is 1 in 3500 births. EA is more frequently observed in boys and in twins. The exact cause of isolated EA remains unknown; a multifactorial etiology, including epigenetic gene expression modifications, is considered. The study included six pairs of twins (three pairs of monozygotic twins and three pairs of dizygotic twins) in which one child was born with EA as an isolated defect, while the other twin was healthy. DNA samples were obtained from the blood and esophageal tissue of the child with EA as well as from the blood of the healthy twin. The reduced representation bisulfite sequencing (RRBS) technique was employed for a whole-genome methylation analysis. The analyses focused on comparing the CpG island methylation profiles between patients with EA and their healthy siblings. Hypermethylation in the promoters of 219 genes and hypomethylation in the promoters of 78 genes were observed. A pathway enrichment analysis revealed the statistically significant differences in methylation profile of 10 hypermethylated genes in the Rho GTPase pathway, previously undescribed in the field of EA (ARHGAP36, ARHGAP4, ARHGAP6, ARHGEF6, ARHGEF9, FGD1, GDI1, MCF2, OCRL, and STARD8).

Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene-Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias.

Skeletal dysplasias (SDs) are a large, heterogeneous group of mostly genetic disorders that affect the bones and cartilage, resulting in abnormal growth and development of skeletal structures. The high clinical and genetic diversity in SDs cause difficulties in prenatal diagnosis. To establish a correct prognosis and better management, it is very important to distinguish SDs with poor life-limiting prognosis or lethal SDs from other ones. Bad prognosis in foetuses is assessed on the basis of the size of the thorax, lung volumes, long bones' length, bones' echogenicity, bones' angulation or presented fractures, and the concomitant presence of non-immune hydrops or visceral abnormalities. To confirm SD diagnosis and perform family genetic consultation, rapid molecular diagnostics are needed; therefore, the NGS method using a panel of genes corresponding to SD or whole-exome sequencing (WES) is commonly used. We report a case of a foetus showing long bones' shortening and a narrow chest with short ribs, diagnosed prenatally with asphyxiating thoracic dystrophy, also known as Jeune syndrome (ATD; OMIM 208500), caused by compound heterozygous variants in the DYNC2H1 gene, identified by prenatally performed rapid-WES analysis. The missense variants in the DYNC2H1 gene were inherited from the mother (c.7289T>C; p.Ile2430Thr) and from the father (c.12716T>G; p.Leu4239Arg). The DYNC2H1 gene is one of at least 17 ATD-associated genes. This disorder belongs to the ninth group of SD, ciliopathies with major skeletal involvement. An extremely narrow, bell-shaped chest, and abnormalities of the kidneys, liver, and retinas were observed in most cases of ATD. Next to lethal and severe forms, clinically mild forms have also been reported. A diagnosis of ATD is important to establish the prognosis and management for the patient, as well as the recurrence risk for the family.

De Novo ATP1A1 Variants in an Early-Onset Complex Neurodevelopmental Syndrome.

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report.

The MYCN oncogene encodes a transcription factor belonging to the MYC family. It is primarily expressed in normal developing embryos and is thought to be critical in brain and other neural development. Loss-of-function variants resulting in haploinsufficiency of MYCN, which encodes a protein with a basic helix-loop-helix domain causes Feingold syndrome (OMIM 164280, ORPHA 391641). We present an occurrence of esophageal atresia (EA) with tracheoesophageal fistula in siblings from a three-generation family affected by variable expressivity of MYCN mutation p.(Ser90GlnfsTer176) as a diagnostic effect of searching the cause of familial esophageal atresia using NGS-based whole-exome sequencing (WES). All of our affected patients showed microcephaly and toe syndactyly, which were frequently reported in the literature. Just one patient exhibited clinodactyly. None of the patients exhibited brachymesophalangy or hypoplastic thumbs. The latest report noted that patients with EA and Feingold syndrome were also those with the more complex and severe phenotype. However, following a thorough review of the present literature, the same association was not found, which is also confirmed by the case we described. The variable phenotypic expression of the patients we described and the data from the literature guide a careful differential diagnosis of Feingold syndrome even in cases of poorly expressed and non-specific symptoms.

Efficacy and safety of sirolimus therapy in familial hypoinsulinemic hypoglycemia caused by AKT2 mutation inherited from the mosaic father.

Activating mutation in the insulin signal-transducing kinase AKT2 results in severe hypoinsulinemic hypoketotic hypoglycemia and a characteristic phenotype of possible overgrowth and, sometimes, acanthosis nigricans. Herein, we describe a metabolic and hormonal profile before and during treatment with sirolimus in two brothers with AKT2 mutation inherited from the mosaic father, who showed low-level mosaicism in sperm. The boys, aged 1 and 14, who had severe non-insulin-dependent hypoketotic hypoglycemia and a typical dysmorphism, were admitted to endocrinology department for the analysis of their metabolic parameters: lipids, lactate, ammonia, glucose, insulin, c-peptide, and hormones (GH, IGF1, IGFBP3, TSH, fT4, cortisol, ACTH) before and during treatment with sirolimus. Previously, they had been treated with high-carbohydrate diet. The brothers were started on sirolimus with subsequent normalization of glycemia and reduced carbohydrate feedings overnight. The lowest fasting glucose levels improved from 20 mg/dl to 45 mg/dl in both sibs. The BMI of both brothers significantly dropped. After 6 months of sirolimus therapy we did not observe any laboratory or clinical side effects of the treatment.

Perinatalna opieka paliatywna realizowana w oddziale polozniczym i neonatologicznym we wspólpracy z hospicjum dla dzieci - doswiadczenia wlasne.

INTRODUCTION: Wady letalne prowadza do wewnatrzmacicznego zgonu plodu lub dziecka bezposrednio po urodzeniu lub we wczesnym okresie niemowlecym, bez wzgledu na zastosowane leczenie. W przypadku wad letalnych nie ma mozliwosci skutecznej pomocy dziecku, mimo postepu mi zeadsytcoysnoyw ania najnowoczesniejszej aparatury lub terapii. Rodzice, którzy decyduja sie na urodzenie dziecka z wada letalna moga byc objeci perinatalna opieka hospicyjna, która ma charakter kompleksowy. Polega ona na wsparciu ciezarnej w okresie przygotowania do porodu, w czasie porodu i po porodzie oraz na wsparciu jej rodziny oraz obejmuje udzielenie rodzicom pelnej informacji o chorobie ich dziecka. Opieka nad dzieckiem po urodzeniu jest nastawiona na ochrone przed uporczywa terapia i zapewnienie dziecku opieki paliatywnej. CEL: Wykazanie znaczenia perinatalnej opieki paliatywnej dla kobiet w ciazy, u których wyniki badan prenatalnych wskazywaly na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu oraz przedstawienie schematu postepowania wedlug modelu wewnatrzszpitalnego hospicjum perinatalnego. MATERIAL I METODY: Analiza retrospektywna objeto dokumentacje 67 pacjentek skierowanych do Programu RAZEM we Wroclawiu w latach 2014-2018 z powodu nieprawidlowych wyników badan prenatalnych (ultrasonograficznych lub/i genetycznych), które wskazywaly na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu. Dokonanoanalizy danych socjodemograficznych, danych klinicznych rozpoznania choroby u plodu, przebiegu ciazy i porodu, trybu postepowania w okresie prenatalnym, podczas porodu i po urodzeniu sie dziecka. WYNIKI: Do Programu zostalo skierowanych 67 kobiet w wieku 20-43 lat (srednio 31,2), które zglaszaly sie w okresie od 15 do 39 tygodnia ciazy (srednio w 25. tygodniu ciazy). Do opieki paliatywnej zakwalifikowano 57 kobiet, czyli 85% skierowanych do programu. Opieke paliatywna kontynuowano u 51 pacjentek, poniewaz 6 kobiet w trakcie procesu diagnostycznego zdecydowalo sie na zakonczenie ciazy (10,5%). Najczestszymi zaburzeniami u plodów byly aberracje chromosomowe, wady OUN i wady nerek. W 95% przypadków doszlo do obumarcia wewnatrzmacicznego plodu lub smierci noworodka. WNIOSKI: Perinatalna opieka paliatywna jest niezbedna forma opieki dla kobiet w ciazy, u których wyniki badan prenatalnych wskazuja na ciezkie zaburzenie rozwojowe u plodu o potencjalnie letalnym rokowaniu. Model wewnatrzszpitalny hospicjum perinatalnego jest korzystna forma opieki, zapewnia jej spójnosc i dobra komunikacje w zespole, co wplywa na dobra jakosc opieki. INTRODUCTION: Lethal defects lead to the intrauterine death of the fetus or the passing away of the child immediately after birth or in early infancy, regardless of the treatment used. In the case of lethal defects, it is not possible to effectively help the child, despite using the most modern equipment or medicines in the treatment or the progress made by medicine. Parents, who decide to continue the pregnancy, although the fetus has a lethal defect that cannot be cured, may be covered by perinatal hospice care, which is comprehensive and consists in supporting the pregnant woman during the prenatal time, during delivery and after delivery and support of her family, giving full information to the parents about their child's illness. Childcare after birth is focused on protecting the infant from persistent therapy and providing him with appropriate conditions. AIM: To demonstrate the role of perinatal palliative care for pregnant women in whom the results of prenatal tests pointed to a severe developmental disorder in the fetus with a potentially lethal prognosis, and to present a pattern of behavior for their hospitalization in the perinatal hospice. MATERIALS AND METHODS: The retrospective analysis included documentation of 67 patients referred to the RAZEM (TOGETHER) Program in Wroclaw in 2014-2018 due to abnormal results of (ultrasound and / or genetic) prenatal tests, which indicated a serious developmental disorder in the fetus with potentially lethal prognosis. Analysis was conducted of sociodemographic data, clinical data on fetal diagnosis, pregnancy and delivery, the procedure for prenatal delivery and postnatal birth. RESULTS: 67 women aged 20-43 years (mean 31.2) were referred to the RAZEM Program. Out of these, 57 women were enrolled for palliative care, which accounted for 85% of those referred to the program. Palliative care was continued in 51 patients, because 6 women decided to terminate their pregnancy during the diagnostic process (10.5%). The most common abnormalities in the fetuses were chromosomal aberrations, CNS defects and kidney defects. In 95% of the cases, intrauterine fetal death or neonatal death occurred. CONCLUSIONS: Perinatal palliative care is an indispensable form of care for pregnant women in whom the results of prenatal tests indicate a serious developmental disorder in the fetus with potentially lethal prognosis. The in-hospital model of a perinatal hospice is a beneficial form of care, as it ensures consistency and good communication in the team, which favourably affects its quality.

Variants of ATP1A3 in residue 756 cause a separate phenotype of relapsing encephalopathy with cerebellar ataxia (RECA)-Report of two cases and literature review.

BACKGROUND: Variants in ATP1A3 cause well-known phenotypes-alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS), and severe early infantile epileptic encephalopathy. Recently, there has been growing evidence for genotype-phenotype correlations in the ATP1A3 variants, and a separate phenotype associated with variants in residue 756-two acronyms are proposed for the moment-FIPWE (fever-induced paroxysmal weakness and encephalopathy) and RECA (relapsing encephalopathy with cerebellar ataxia). MATERIALS AND METHODS: Herein, we are describing two new pediatric cases with a p.Arg756His change in the ATP1A3 gene. Both patients have had more than one episode of a neurological decompensation triggered by fever with severe hypotonia and followed by ataxia. Thirty-three cases from literature were analyzed to define and strengthen the genotype-phenotype correlation of variants located in residue 756 (p.Arg756His, p.Arg756Cys, p.Arg756Leu). CONCLUSIONS: Patients with a ATP1A3 variant in residue 756 are characterized by recurrent paroxysmal episodes of neurological decompensations triggered by fever, with severe hypotonia, ataxia, dysarthria, symptoms from the orofacial area (dysphagia, drooling) as well as with altered consciousness. Recovery is slow and usually not full with the persistent symptoms of cerebellar ataxia, dysarthria, dystonic and choreiform movements.

Prenatal Versus Postnatal Diagnosis of Meckel-Gruber and Joubert Syndrome in Patients with TMEM67 Mutations.

Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of single-gene disorders in the prenatal period. Two patients with a prenatal diagnosis of polycystic kidney disease are presented in this article. TMEM67 mutations were identified in both fetuses using a whole-exome sequencing (WES) study. In one of them, the phenotypic syndrome diagnosed prenatally was different from that diagnosed in the postnatal period.

Lethal and life-limiting skeletal dysplasias: Selected prenatal issues.

Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups. The incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The type of dysplasia and associated abnormalities affect the lethality, survival and long-term prognosis of skeletal dysplasias. It is crucial to distinguish skeletal dysplasias and correctly diagnose the disease to establish the prognosis and achieve better management. It is possible to use prenatal ultrasonography to observe predictors of lethality, such as a bell-shaped thorax, short ribs, severe femoral shortening, and decreased lung volume. Individual lethal or life-limiting dysplasias may have more or less specific features on prenatal ultrasound. The prenatal features of the most common skeletal dysplasias, such as thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, and campomelic dysplasia, are discussed in this article. Less frequent dysplasias, such as asphyxiating thoracic dystrophy, fibrochondrogenesis, atelosteogenesis, and homozygous achondroplasia, are also discussed.

Case Report: Further Delineation of Neurological Symptoms in Young Children Caused by Compound Heterozygous Mutation in the PIEZO2 Gene.

PIEZO2 protein is a unique ion channel that converts mechanical impulses into cellular signals in somatosensory neurons and is involved in various mechanotransduction pathways. The recessive PIEZO2 loss-of-function pathogenic variants are associated with distal arthrogryposis with impaired proprioception and touch (DAIPT). Here we present three new DAIPT patients. The genetic diagnosis was established by exome sequencing and let us to identify 6 novel loss-of-function PIEZO2 variants: four splicing (c.1080+1G>A, c.4092+1G>T, c.6355+1G>T, and c.7613+1G>A), one nonsense (c.6088C>T) and one frameshift variant (c.6175_6191del) for which mosaic variant was identified in proband's mother. All patients presented typical symptoms at birth, with congenital contractures, bilateral hip dislocation/dysplasia, generalized hypotonia, transient feeding and difficulties. Two were afflicted by transient respiratory insufficiency. In all children motor development was severely delayed. In one patient, severe cognitive delay was also observed. Moreover, among the cases described by us there is the youngest diagnosed child to date.

Kabuki Syndrome-Clinical Review with Molecular Aspects.

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.

Further Delineation of Phenotype and Genotype of Primary Microcephaly Syndrome with Cortical Malformations Associated with Mutations in the WDR62 Gene.

Type 2 congenital microcephaly (MCPH2) is a brain development disorder characterized by primary microcephaly with or without brain malformations. MCPH2 is caused by mutations in the WDR62 gene. We present three new patients with MCPH2 and compound heterozygous mutations in the WDR62 gene. In all the cases, the parents were healthy and unrelated. All children were clinically diagnosed with congenital microcephaly and retardation of motor and speech development. Sequencing results in the presented patients revealed five new variants in the WDR62 gene (c.4273C>T, c.1711_1712insTA, c.1777_1778delGA, c.1642+2T>G, c.194T>A) and one previously described in the German population (c.2864_2867delACAG). In two of the presented cases, variants in the SMAD4, DKC1, and ATRX genes were also found with unknown effects on the course of the disease. Moreover, in the article we collected and compared the most common clinical symptoms, dysmorphic features, and changes in radiographic examinations of the brain observed in 120 patients with recessive primary microcephaly type 2 caused by mutations in the WDR62 gene.

Interfamilial clinical variability in four Polish families with cranioectodermal dysplasia and identical compound heterozygous variants in WDR35.

Cranioectodermal dysplasia (CED) is a rare autosomal recessive disorder primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. CED is a chondrodysplasia, which is part of a spectrum of clinically and genetically heterogeneous diseases that result from disruptions in cilia. Pathogenic variants in genes encoding components of the ciliary transport machinery are known to cause CED. Intra- and interfamilial clinical variability has been reported in a few CED studies and the findings of this study align with these observations. Here, we report on five CED patients from four Polish families with identical compound heterozygous variants [c.1922T>G p.(Leu641Ter) and c.2522A>T; p.(Asp841Val)] in WDR35. The frequent occurrence of both identified changes in Polish CED families suggests that these variants may be founder mutations. Clinical evaluation of the CED patients revealed interfamilial clinical variability among the patients. This includes differences in skeletal and ectodermal features as well as variability in development, progression, and severity of renal and liver insufficiency. This is the first report showing significant interfamilial clinical variability in a series of CED patients from unrelated families with identical compound heterozygous variants in WDR35. Our findings strongly indicate that other genetic and non-genetic factors may modulate the progression and expression of the patients' phenotypes.

Broad phenotypic spectrum of germ line 7p12.1 microdeletions encompassing the IKZF1 gene includes predisposition to acute lymphoblastic leukemia.

Microdeletions of 7p12.1 encompassing the IKZF1 gene locus are rare, with few cases reported. The common phenotype includes intellectual disability, overgrowth, and facial dysmorphism accompanied, albeit rarely, by congenital anomalies. Haploinsufficiency of IKZF1 predisposes individuals to childhood acute lymphoblastic leukemia (ALL). In this study, we comprehensively analyzed the frequency of 7p12.1 deletions among 4581 Polish individuals who underwent chromosomal microarray testing for unexplained developmental delay, intellectual disability, and/or congenital anomalies. Two unrelated individuals (0.04%) with a de novo interstitial 7p12.1 microdeletion encompassing IKZF1 were identified. One developed ALL. Analysis of the incidence and the phenotype of constitutional 7p12.1 microdeletion, which based on the previously annotated patients data in public databases and literature reports, revealed 21 cases including five patients diagnosed with ALL.

Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

AP4B1-associated hereditary spastic paraplegia: expansion of phenotypic spectrum related to homozygous p.Thr387fs variant.

Biallelic mutations in the AP4B1 gene, encoding adaptor-related protein complex 4 beta-1 subunit, have been recognized as an important cause of a group of conditions leading to adaptor-related protein complex 4 (AP4)-associated hereditary spastic paraplegia (SPG47). We describe a homozygous, known variant c.1160_1161delCA (p.Thr387fs) that was found in the largest ever group of patients coming from four families. The patients exhibited early hypotonia progressing to spastic paraplegia, microcephaly, epilepsy, and central nervous system (CNS) defects and global developmental delay that are consistent with the nature of SPG47. Our findings expand phenotypic spectrum of SPG47 to include polymorphic seizures, mild/moderate intellectual disability, and intracerebral cysts as well as point to founder mutation in AP4 deficiency disorders in apparently non-consanguineous Polish families without shared ancestry.

The Impact of Congenital Esophageal Atresia on the Family Functioning.

PURPOSE: Most of the research in the field of esophageal atresia (EA) is focused on diagnostic problems and surgery. There is scarce literature addressing the impact of EA on the lives of families of patients. The aim of this paper is to investigate whether the presence of underlying associated malformations, disease-specific feeding problems and prematurity would have a significant influence on the family of a child after surgical repair of EA. DESIGN AND METHODS: The study sample consisted of 73 participants who were parents of children after surgery of EA. The impact of EA on families was assessed using an Authors-Designed Questionnaire (ADQ) to collect medical and sociodemographic background data as well as standardized questionnaire: the PedsQL™ Family Impact Module (PedsQL-FIM). RESULTS: The presence of cardiac impairment significantly (p = 0.037) affects the functioning of the family in the emotional domain. The coexistence of skeletal impairment seems to have the greatest impact on the functioning of the family, three statistically significant correlations have been demonstrated: (p = 0.021) - in the social domain, (p = 0.009) - in the cognitive domain and (p = 0.023) - in the domain of communication. The families of patients with tracheoesophageal fistula (TEF) had the statistically lower (p < 0.05) score of functioning in the emotional domain than those with children without TEF. CONCLUSION: Feeding problems and the presence of associated anomalies significantly affect the functioning of the family of the child with EA.

DNA methylation abundantly associates with fetal alcohol spectrum disorder and its subphenotypes.

Aim: Fetal alcohol spectrum disorder (FASD) involves prenatal growth delay, impaired facial and CNS development and causes severe clinical, social-economic burdens. Here, we aim to detect DNA-methylation aberrations associated with FASD and potential FASD diagnostic and prognostic biomarkers. Patients & methods: The FASD diagnosis was established according to golden-standard protocols in a discovery and independent replication cohort. Genome-wide differential methylation association and replication analyses were performed. Results: We identified several loci that were robustly associated with FASD or one of its sub phenotypes. Our findings were evaluated using previously reported genome-wide surveys. Conclusion: We have detected robust FASD associated differentially methylated positions and differentially methylated regions for FASD in general and for FASD subphenotypes, in other words on growth delay, impaired facial and CNS development.