Intellectual and Behavioral Phenotypes of Smith–Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant

Aim: Smith–Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the RAI1 gene. SMS is associated with developmental delay, intellectual disability (ID), and major sleep and behavioral disturbances. To explore how genetic variants may affect intellectual functioning and behavior, we compared intellectual and behavioral phenotypes between individuals with a 17p11.2 deletion and pathogenic RAI1 variant. Method: We reviewed available clinical records from individuals (aged 0–45 years) with SMS, ascertained through a Dutch multidisciplinary SMS specialty clinic. Results: We included a total of 66 individuals (n = 47, 71.2% with a 17p11.2 deletion and n = 19, 28.8% with a pathogenic RAI1 variant) for whom data were available on intellectual functioning, severity of ID (n = 53), and behavioral problems assessed with the Child Behavior Checklist (CBCL, n = 39). Median full-scale IQ scores were lower (56.0 vs. 73.5, p = 0.001) and the proportion of individuals with more severe ID was higher (p = 0.01) in the 17p11.2 deletion group. Median total CBCL 6–18 scores (73.5 vs. 66.0, p = 0.02) and scores on the sub-scales somatic complaints (68.0 vs. 57.0, p = 0.001), withdrawn/depressed behavior (69.5 vs. 55.0, p = 0.02), and internalizing behavior (66.0 vs. 55.0, p = 0.002) were higher in the RAI1 group. Conclusion: The results of this study suggest that 17p11.2 deletions are associated with a lower level of intellectual functioning and less internalizing of problems compared to pathogenic RAI1 variants. The findings of this study may contribute to personalized-management strategies in individuals with SMS

Genotype-phenotype correlation in adult-onset acid maltase deficiency

We performed a clinical, biochemical, and genetic study in 16 patients from 11 families with adult‐onset acid maltase deficiency. All patients were compound heterozygotes and carried the IVS1(– 13T→G) transversion on one allele; the second allele harbored either a deletion of a T at position 525 in exon 2 (7 probands, 64%) or a deletion of exon 18 (1 proband, 9%). Detrioration of handicap was related to age, and decrease in vital capacity to duration of the symptomatic stage. Respiratory insufficiency was never the first manifestation. The levels of activity of serum creatine kinase and of β‐glucosidase in peripheral blood cells or muscle were helpful for the diagnosis, but did not have prognostic value. The adult form of acid maltase deficiency appears to be both clinically and genetically rather homogeneous; decrease of β‐glucosidase activity is the final common pathway leading to destruction of muscle fibers and progression of muscle weakness over a period of years. Copyrigh

Genetic outcomes in children with developmental language disorder: a systematic review

INTRODUCTION: Developmental language disorder (DLD) is a common childhood condition negatively influencing communication and psychosocial development. An increasing number of pathogenic variants or chromosomal anomalies possibly related to DLD have been identified. To provide a base for accurate clinical genetic diagnostic work-up for DLD patients, understanding the specific genetic background is crucial. This study aims to give a systematic literature overview of pathogenic variants or chromosomal anomalies causative for DLD in children. METHODS: We conducted a systematic search in PubMed and Embase on available literature related to the genetic background of diagnosed DLD in children. Included papers were critically appraised before data extraction. An additional search in OMIM was performed to see if the described DLD genes are associated with a broader clinical spectrum. RESULTS: The search resulted in 15,842 papers. After assessing eligibility, 47 studies remained, of which 25 studies related to sex chromosome aneuploidies and 15 papers concerned other chromosomal anomalies (SCAs) and/or Copy Number Variants (CNVs), including del15q13.1-13.3 and del16p11.2. The remaining 7 studies displayed a variety of gene variants. 45 (candidate) genes related to language development, including FOXP2, GRIN2A, ERC1, and ATP2C2. After an additional search in the OMIM database, 22 of these genes were associated with a genetic disorder with a broader clinical spectrum, including intellectual disability, epilepsy, and/or autism. CONCLUSION: Our study illustrates that DLD can be related to SCAs and specific CNV's. The reported (candidate) genes ( n  = 45) in the latter category reflect the genetic heterogeneity and support DLD without any comorbidities and syndromic language disorder have an overlapping genetic etiology

Genetic outcomes in children with developmental language disorder: a systematic review

INTRODUCTION: Developmental language disorder (DLD) is a common childhood condition negatively influencing communication and psychosocial development. An increasing number of pathogenic variants or chromosomal anomalies possibly related to DLD have been identified. To provide a base for accurate clinical genetic diagnostic work-up for DLD patients, understanding the specific genetic background is crucial. This study aims to give a systematic literature overview of pathogenic variants or chromosomal anomalies causative for DLD in children. METHODS: We conducted a systematic search in PubMed and Embase on available literature related to the genetic background of diagnosed DLD in children. Included papers were critically appraised before data extraction. An additional search in OMIM was performed to see if the described DLD genes are associated with a broader clinical spectrum. RESULTS: The search resulted in 15,842 papers. After assessing eligibility, 47 studies remained, of which 25 studies related to sex chromosome aneuploidies and 15 papers concerned other chromosomal anomalies (SCAs) and/or Copy Number Variants (CNVs), including del15q13.1-13.3 and del16p11.2. The remaining 7 studies displayed a variety of gene variants. 45 (candidate) genes related to language development, including FOXP2, GRIN2A, ERC1, and ATP2C2. After an additional search in the OMIM database, 22 of these genes were associated with a genetic disorder with a broader clinical spectrum, including intellectual disability, epilepsy, and/or autism. CONCLUSION: Our study illustrates that DLD can be related to SCAs and specific CNV's. The reported (candidate) genes ( n  = 45) in the latter category reflect the genetic heterogeneity and support DLD without any comorbidities and syndromic language disorder have an overlapping genetic etiology

Gastrointestinal symptoms in patients with isolated oligodontia and a Wnt gene mutation

OBJECTIVE: Since Wnt signaling plays an important role in both tooth agenesis and altered intestine homeostasis, the aim was to compare gastrointestinal symptoms in patients with isolated oligodontia caused by a Wnt pathway gene mutation and controls. METHODS: A case-control study was designed to compare self-reported gastrointestinal symptoms among patients with isolated oligodontia, caused by a Wnt signaling gene mutation, and fully dentate controls. The Gastrointestinal Symptom Rating Scale (GSRS) was used to assess gastrointestinal symptoms. Prevalence and severity of gastrointestinal symptoms among patients and age- and gender-matched controls was evaluated. RESULTS: Twenty patients with isolated oligodontia and a pathogenic variant in the wnt pathway genes WNT10A, LRP6 or PAX9 participated. The prevalence of gastrointestinal symptoms was higher in the oligodontia patients compared to their controls (Χ2 (1) = 87.33, p = .008). Mean GSRS total scores (p = .011) and domain scores for 'abdominal pain' (p = .022), 'reflux' (p = .003) and constipation (p = .030) were higher for these oligodontia patients compared to their controls. CONCLUSION: Gastrointestinal symptoms are more prevalent and more severe in patients with isolated oligodontia and a deficiency in a Wnt pathway related gene, when compared to controls without tooth agenesis

Genetic outcomes in children with developmental language disorder: a systematic review

IntroductionDevelopmental language disorder (DLD) is a common childhood condition negatively influencing communication and psychosocial development. An increasing number of pathogenic variants or chromosomal anomalies possibly related to DLD have been identified. To provide a base for accurate clinical genetic diagnostic work-up for DLD patients, understanding the specific genetic background is crucial. This study aims to give a systematic literature overview of pathogenic variants or chromosomal anomalies causative for DLD in children.MethodsWe conducted a systematic search in PubMed and Embase on available literature related to the genetic background of diagnosed DLD in children. Included papers were critically appraised before data extraction. An additional search in OMIM was performed to see if the described DLD genes are associated with a broader clinical spectrum.ResultsThe search resulted in 15,842 papers. After assessing eligibility, 47 studies remained, of which 25 studies related to sex chromosome aneuploidies and 15 papers concerned other chromosomal anomalies (SCAs) and/or Copy Number Variants (CNVs), including del15q13.1–13.3 and del16p11.2. The remaining 7 studies displayed a variety of gene variants. 45 (candidate) genes related to language development, including FOXP2, GRIN2A, ERC1, and ATP2C2. After an additional search in the OMIM database, 22 of these genes were associated with a genetic disorder with a broader clinical spectrum, including intellectual disability, epilepsy, and/or autism.ConclusionOur study illustrates that DLD can be related to SCAs and specific CNV's. The reported (candidate) genes (n = 45) in the latter category reflect the genetic heterogeneity and support DLD without any comorbidities and syndromic language disorder have an overlapping genetic etiology

HNRNPH1 ‐related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related intellectual disability

Trends in quality of care and dying perceived by family caregivers of nursing home residents with dementia 2005-2019

BACKGROUND: Dementia palliative care is increasingly subject of research and practice improvement initiatives. AIM: To assess any changes over time in the evaluation of quality of care and quality of dying with dementia by family caregivers. DESIGN: Combined analysis of eight studies with bereaved family caregivers’ evaluations 2005–2019. SETTING/PARTICIPANTS: Family caregivers of nursing home residents with dementia in the Netherlands (n = 1189) completed the End-of-Life in Dementia Satisfaction With Care (EOLD-SWC; quality of care) and Comfort Assessment in Dying (EOLD-CAD, four subscales; quality of dying) instruments. Changes in scores over time were analysed using mixed models with random effects for season and facility and adjustment for demographics, prospective design and urbanised region. RESULTS: The mean total EOLD-SWC score was 33.40 (SD 5.08) and increased by 0.148 points per year (95% CI, 0.052–0.244; adjusted 0.170 points 95% CI, 0.055–0.258). The mean total EOLD-CAD score was 30.80 (SD 5.76) and, unadjusted, there was a trend of decreasing quality of dying over time of −0.175 points (95% CI, −0.291 to −0.058) per year increment. With adjustment, the trend was not significant (−0.070 EOLD-CAD total score points, 95% CI, −0.205 to 0.065) and only the EOLD-CAD subscale ‘Well being’ decreased. CONCLUSION: We identified divergent trends over 14 years of increased quality of care, while quality of dying did not increase and well-being in dying decreased. Further research is needed on what well-being in dying means to family. Quality improvement requires continued efforts to treat symptoms in dying with dementia