The first study of 3-M Syndrome in Jordan and Literature Review

The prevalence of 3-M syndrome remains unclear owing to its rarity and the limited number of reported cases in the medical literature. To date, approximately 100 cases of the disorder have been documented in MedlinePlus Genetics. Here, we present the first case study report from Jordan of a boy diagnosed with 3-M syndrome at 9 months of age via karyotyping. The patient exhibited distinct facial features, severe prenatal and postnatal growth retardation, and normal mental development. As rare genetic autosomal recessive mutations are common where consanguineous marriages are prevalent, raising awareness of such rare genetic diseases is critical. This paper aims to provide a case report on 3-M syndrome and a literature review. (AU)

Atypical Presentation of Lip Nodules in Clinically Diagnosed Juvenile Hyaline Fibromatosis.

Juvenile hyaline fibromatosis (JHF) is a rare, hereditary disease characterized by abnormal hyaline deposits within the skin, soft tissues, joints, and bones. The condition itself is often debilitating, with no curative treatment available. A definitive diagnosis is established by genetic testing. However, the hallmarks of gingival hypertrophy, subcutaneous scalp nodules, and joint contractures can be used as a clinical guide when genetic testing is unavailable. Here, we report an unusual case of a five-year-old child clinically diagnosed with juvenile hyaline fibromatosis with atypical nodules exclusively confined to the perioral region.

Mucopolysaccharidosis Type VI with Recurrent Chest Infection.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) is a progressive multi-systemic autosomal recessive disease resulting from a deficiency of arylsulfatase B (N-acetylgalactosamine-4-sulfatase). Here we report the case of a three-year-old male child born full-term via normal vaginal delivery. He had frequent admissions due to a chest infection that started at two months of age. At the age of 23 months, he was admitted after complaining of shortness of breath (SOB) due to asthma and aspiration pneumonia; additionally, dysmorphic features were noticed (single palmar crease, short round toes, coarse facial features such as a flat nose, big lips). A genetic study showed mucopolysaccharidosis VI (MPS VI). At three years of age, he was complaining of cough and SOB. Examination showed wheezing all over the chest, normal first and second heart sounds (S1 and S2), a murmur with no clicks, hepatosplenomegaly, and a palpable left kidney. However, the central nervous system (CNS) and eye examinations were normal. Echocardiography revealed a thickened bicuspid aortic valve, mild aortic regurgitation, and mitral regurgitation. Therefore, the patient presented with different clinical symptoms of MPS VI. It is important to increase the physicians' awareness about MPS by focusing on increasing the probability of MPS as a differential diagnosis whenever patients present with abnormal appearance, limb deformities, and recurrent unexplained infections; hence, making early diagnosis and treatment decisions, leading to a slowing down of the progression of the disease and enhancing the patient's quality of life.

A novel homozygous missense mutation in L-2-HGA gene: A case report.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare autosomal recessive disease resulted from the mutated gene L-2- hydroxyglutarate dehydrogenase (L2HGDH). We presented a female case who inherited the disease from her consanguineous relatives and suffered from cognitive impairment, seizure, and ataxia. Using cerebral magnetic resonance imaging (MRI), urine organic acid test, and high-throughput DNA sequencing, a novel homozygous missense mutation was found in the L2HGDH gene, namely c 0.847 G>A/p. G283R in exon 7. Summarizing the clinical information of the patient with L-2-HGA exhibited to be beneficial for the diagnosis of this rare disease. In summary, the pathogenic missense mutation in the case was reliably confirmed using the bioinformatics analysis.

Fulminant Viral Hepatitis in Two Siblings with Inherited IL-10RB Deficiency.

Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses.

Couple screening for recessively inherited disorders.

Couple screening aims to identify couples with an increased risk of having a child affected with an autosomal recessive or X-linked disorder, in order to facilitate informed reproductive decision making. Both expectant parents should be screened as a single entity, instead of individual testing. Carrier testing was typically performed for a few relatively common recessive disorders associated with significant morbidity, reduced life expectancy and often because of a considerably higher carrier frequency in a specific population for certain diseases. However, new genetic testing technologies enable the expansion of screening to multiple conditions, genes and sequence variants. There are multiple reproductive options for screening couples at risk, particularly when genetic traits are detected in the preconception period.

A Novel Mutation in the NAGLU (N-Acetyl-Alpha-Glucosaminidase) Gene Associated With Mucopolysaccharidosis Type III-B in a Saudi Girl.

Mucopolysaccharidosis type III-B (MPS III), also known as Sanfilippo syndrome, is a rare autosomal recessive lysosomal storage disease that primarily affects the brain and spinal cord. In this report, we describe the case of an eight-year-old female child who presented to the emergency room with an asthma exacerbation. She had coarse facial features, thick eyebrows, deep-seated eyes, thinning coarse hair, and macrocephaly. Moreover, she suffered from hepatosplenomegaly, generalized muscular atrophy, global developmental delay, and scoliosis. Urinary glycosaminoglycans (GAGs) were within normal limits. Full genetic testing confirmed the diagnosis of Sanfilippo syndrome type B with a deficiency of alpha-N-acetylglucosaminidase caused by a homozygous mutation c.889C>T, p.(Arg297*) in the NAGLU (N-acetyl-alpha-glucosaminidase) gene. Chromosomal microarray analysis (CMA) showed a copy number variant (CNV) within the 1q24 region. Thus far, CNVs similar in size and position have not been reported in the literature, making this a novel mutation.

Expert consensus on diagnosis and treatment of very long-chain acyl-CoA dehydrogenase deficiency.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a metabolic disease of long chain fatty acid oxidation. The clinical manifestations are heterogeneous, mainly with heart, liver, skeletal muscle and brain damage, and the onset of which can be from newborn to adult. Cardiomyopathy type is more serious with high mortality. The liver failure type and myopathy type would be potentially lethal, but generally the prognosis is relatively good. Recurrent hypoglycemia, energy metabolism disorder, liver dysfunction, cardiomyopathy and serious arrhythmia are the main causes of death. Most patients can be identified through neonatal screening, and the prognosis is usually good in patients with early diagnosis and treatment. The purpose of this consensus is to standardize the diagnosis, treatment and management of VLCAD deficiency, so as to improve the prognosis of patients and reduce death and disability.

Carrier detection probabilities for autosomal recessive variants in unrelated and consanguineous couples - an evaluation of the 86 genes of the ACMG 'Tier 3' panel.

Carrier screening for autosomal recessive variants has become a cornerstone of community and public health genetics. While the first carrier screening programs were confined to conditions with relatively high prevalence, and hence well-known carrier frequency, the number of candidate genes has increased greatly since the advent of high-throughput DNA sequencing technologies. The epidemiological database of the ensuing gene panels is mostly sparse, and judgement of their performance is, therefore, anything but straightforward. We therefore derived estimates of the carrier detection probabilities among non-consanguineous and consanguineous couples as expected using the 'Tier 3' carrier screening gene panel recently recommended by the American College of Medical Genetics (ACMG). For non-Finnish Europeans, the respective estimate for unrelated couples equals 0.63%, implying that the ACMG Tier 3 panel accounts for over 90% of the genetic load for autosomal recessive diseases in this population. Among the offspring of first cousins, the corresponding incidence is expected to be tenfold higher, an increase still consistent with previous estimates of the overall risk of birth defects for this type of mating. Our considerations are intended to aid the implementation of carrier screening programs and to provide additional support to reproductive counselling and to obtaining informed consent.

LMOD2-related dilated cardiomyopathy presenting in late infancy.

Leiomodin-2 (LMOD2) is an important regulator of the thin filament length, known to promote elongation of actin through polymerization at pointed ends. Mice with Lmod2 deficiency die around 3 weeks of age due to severe dilated cardiomyopathy (DCM), resulting from decreased heart contractility due to shorter thin filaments. To date, there have been three infants from two families reported with biallelic variants in LMOD2, presenting with perinatal onset DCM. Here, we describe a third family with a child harboring a previously described homozygous frameshift variant, c.1243_1244delCT (p.L415Vfs*108) with DCM, presenting later in infancy at 9 months of age. Family history was relevant for a sibling who died suddenly at 1 year of age after being diagnosed with cardiomegaly. LMOD2-related cardiomyopathy is a rare form of inherited cardiomyopathy resulting from thin filament length dysregulation and should be considered in genetic evaluation of newborns and infants with suspected autosomal recessive inheritance or sporadic early onset cardiomyopathy.

Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity.

Recurrence risk calculations in autosomal recessive diseases are complicated when the effect of genetic variants and their population frequencies and penetrances are unknown. An example of this is Stargardt disease (STGD1), a frequent recessive retinal disease caused by bi-allelic pathogenic variants in ABCA4. In this cross-sectional study, 1,619 ABCA4 variants from 5,579 individuals with STGD1 were collected and categorized by (1) severity based on statistical comparisons of their frequencies in STGD1-affected individuals versus the general population, (2) their observed versus expected homozygous occurrence in STGD1-affected individuals, (3) their occurrence in combination with established mild alleles in STGD1-affected individuals, and (4) previous functional and clinical studies. We used the sum allele frequencies of these severity categories to estimate recurrence risks for offspring of STGD1-affected individuals and carriers of pathogenic ABCA4 variants. The risk for offspring of an STGD1-affected individual with the "severe|severe" genotype or a "severe|mild with complete penetrance" genotype to develop STGD1 at some moment in life was estimated at 2.8%-3.1% (1 in 36-32 individuals) and 1.6%-1.8% (1 in 62-57 individuals), respectively. The risk to develop STGD1 in childhood was estimated to be 2- to 4-fold lower: 0.68%-0.79% (1 in 148-126) and 0.34%-0.39% (1 in 296-252), respectively. In conclusion, we established personalized recurrence risk calculations for STGD1-affected individuals with different combinations of variants. We thus propose an expanded genotype-based personalized counseling to appreciate the variable recurrence risks for STGD1-affected individuals. This represents a conceptual breakthrough because risk calculations for STGD1 may be exemplary for many other inherited diseases.

New progress in the diagnosis and treatment of thiamine responsive megaloblastic anemia syndrome / 中华实用儿科临床杂志

Thiamine responsive megaloblastic anemia syndrome is a rare autosomal recessive disease caused by mutations of the SLC19A2 gene that encodes the high-affinity thiamine transporter-1.Thiamine responsive megaloblastic anemia syndrome involves extensive organs and systems with various clinical manifestations.The typical triad is megaloblastic anemia, non-autoimmune diabetes, and sensorineural deafness.The diagnosis of thiamine responsive megaloblastic anemia syndrome depends on the detection of the pathogenic gene SLC19A2.Thiamine replacement therapy is the first-line treatment.Blood glucose of patients with thiamine responsive megaloblastic anemia syndrome should be comprehensively managed, and hearing aids and cochlear implants can be used to improve the hearing.

Consensus on diagnosis and treatment of very long-chain acyl-CoA dehydrogenase deficiency / 浙江大学学报·医学版

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a metabolic disease of long chain fatty acid oxidation. The clinical manifestations are heterogeneous, mainly with heart, liver, skeletal muscle and brain damage, and the onset of which can be from newborn to adult. Cardiomyopathy type is more serious with high mortality. The liver failure type and myopathy type would be potentially lethal, but generally the prognosis is relatively good. Recurrent hypoglycemia, energy metabolism disorder, liver dysfunction, cardiomyopathy and serious arrhythmia are the main causes of death. Most patients can be identified through neonatal screening, and the prognosis is usually good in patients with early diagnosis and treatment. The purpose of this consensus is to standardize the diagnosis, treatment and management of VLCAD deficiency, so as to improve the prognosis of patients and reduce death and disability.

Maximal Segmental Score Method for Localizing Recessive Disease Variants Based on Sequence Data.

BACKGROUND: Due to the affordability of whole-genome sequencing, the genetic association design can now address rare diseases. However, some common statistical association methods only consider homozygosity mapping and need several criteria, such as sliding windows of a given size and statistical significance threshold setting, such as P-value < 0.05 to achieve good power in rare disease association detection. METHODS: Our region-specific method, called expanded maximal segmental score (eMSS), converts p-values into continuous scores based on the maximal segmental score (MSS) (Lin et al., 2014) for detecting disease-associated segments. Our eMSS considers the whole genome sequence data, not only regions of homozygosity in candidate genes. Unlike sliding window methods of a given size, eMSS does not need predetermined parameters, such as window size or minimum or maximum number of SNPs in a segment. The performance of eMSS was evaluated by simulations and real data analysis for autosomal recessive diseases multiple intestinal atresia (MIA) and osteogenesis imperfecta (OI), where the number of cases is extremely small. For the real data, the results by eMSS were compared with a state-of-the-art method, HDR-del (Imai et al., 2016). RESULTS: Our simulation results show that eMSS had higher power as the number of non-causal haplotype blocks decreased. The type I error for eMSS under different scenarios was well controlled, p < 0.05. For our observed data, the bone morphogenetic protein 1 (BMP1) gene on chromosome 8, the Violaxanthin de-epoxidase-related chloroplast (VDR) gene on chromosome 12 associated with OI, and the tetratricopeptide repeat domain 7A (TTC7A) gene on chromosome 2 associated with MIA have previously been identified as harboring the relevant pathogenic mutations. CONCLUSIONS: When compared to HDR-del, our eMSS is powerful in analyzing even small numbers of recessive cases, and the results show that the method can further reduce numbers of candidate variants to a very small set of susceptibility pathogenic variants underlying OI and MIA. When we conduct whole-genome sequence analysis, eMSS used 3/5 the computation time of HDR-del. Without additional parameters needing to be set in the segment detection, the computational burden for eMSS is lower compared with that in other region-specific approaches.

A Novel Cadherin 23 Variant for Hereditary Hearing Loss Reveals Additional Support for a DFNB12 Nonsyndromic Phenotype of CDH23.

BACKGROUND AND OBJECTIVES: Identification of the pathogenic mutations underlying hereditary hearing loss (HL) is difficult, since causative mutations in 60 different genes have so far been reported. METHODS: A comprehensive clinical and pedigree examination was performed on a multiplex family suffering from HL. Direct sequencing of GJB2 and genetic linkage analysis of 5 other most common recessive nonsyndromic HL (ARNSHL) genes were accomplished. Next-generation sequencing (NGS) was utilized to reveal the possible genetic etiology of the disease. RESULTS: NGS results showed a novel rare variant c.2977G>A (p.Asp993Asn) in the CDH23 gene. The variant, which is a missense in exon 26 of the CDH23 gene, fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. Electroretinography rejects the Usher syndrome in the family. CONCLUSIONS: The present study shows that an accurate molecular diagnosis based on NGS technologies largely improves molecular-diagnostic outcome and thus genetic counseling, and helps to clarify the recurrence risk in deaf families.

Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy.

PURPOSE: To evaluate the clinical phenotype of autosomal recessive NR2E3-related retinal dystrophy. METHODS: We retrospectively studied 11 patients carrying out at least 2 NR2E3 mutations; they had undergone comprehensive ophthalmological examination, fundus photography, optical coherence tomography, electrophysiological testing, and visual field at the Regional Reference Center for Hereditary Retinal Degenerations of the Eye Clinic in Florence. RESULTS: Five females and six males with a diagnosis of NR2E3-related retinal dystrophy were included in the study. All patients complained of nyctalopia. Visual acuity ranged from 0.00 logMAR to hand motion. Two patients presented bull's eye maculopathy, and one of these was characterized by a triple hyper-autofluorescent ring at the fundus autofluorescence examination. Three patients showed small yellowish dots and spots at the mid-periphery. One patient was characterized by widespread subretinal drusenoid deposits (SDD) at the posterior pole. Four patients showed vitreous abnormalities. Optical coherence tomography (OCT) examinations detected variable degrees of abnormal retinal lamination and schitic changes. Seven patients were compound heterozygous and four were homozygous for mutations in NR2E3. CONCLUSIONS: Our study confirmed high variable phenotype in autosomal recessive NR2E3-related retinal dystrophy. Bull's eye maculopathy, subretinal drusenoid deposits, and foveal hypoplasia represent novel clinical findings in NR2E3-related retinal dystrophy. Macular involvement was detectable in all the patients, and the abnormal foveal avascular zone (FAZ) supports the role of NR2E3 in retinal development.

Spondylocostal Dysostosis (Jarcho-Levin Syndrome) in an Adult Patient with Consanguineous Parents, in Long-Term Follow-Up.

A 24-year-old woman presented to neurosurgical consultation for chronic back pain. The patient was long term in wheelchair for vertebral deformity. She was the third child of first-degree consanguineous parents. The 2 older brothers had also vertebral malformations. The radiological images showed butterfly vertebra, vertebral fusion, hemivertebrae, scoliosis, and rib malformation. The patient was in follow-up for restrictive lung disease. Motor evoked potentials and lower limb electromyography were normal. We recommended conservative treatment for the back pain with antalgic and physical therapy. Diagnosis of spondylocostal dysostosis, or Jarcho-Levin syndrome, was made based on radiological features. Radiological mages are pathognomonic. Spondylocostal dysostosis is a rare hereditary disorder associated with multiple vertebral and rib anomalies. The entity is distinct from spondylothoracic dysostosis, which has a higher mortality due to respiratory complications. The patient was not compliant for genetic familiar counseling. At 12-year follow-up, the patient was in periodic respiratory and motor rehabilitation therapy.

Are Lethal Alleles Too Abundant in Humans?

Across species, many individuals carry one or more recessive lethal alleles, posing an evolutionary conundrum for their persistence. Using a population genomic approach, Amorim et al. studied the abundance of lethal disease-causing mutations in humans and found that, while appearing more common than expected, most may nonetheless persist at frequencies predicted by mutation-selection balance.

Chediak-Higashi Syndrome: A Case Series from Karnataka, India.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease, characterized by partial oculocutaneous albinism, frequent pyogenic infections, and the presence of abnormal large granules in leukocytes and other granulecontaining cells. The abnormal granules are readily seen in blood and marrow granulocytes. Other clinical features include silvery hair, photophobia, nystagmus and hepatosplenomegaly. However, the presence of abnormal giant intracytoplasmic granules in neutrophils and their precursors are diagnostic of CHS. Here, we present a series of five cases, out of which four presented in the accelerated phase. In all the five cases, the giant granules were noted predominantly in the cytoplasm of lymphocytes, which is a rare occurrence compared to those present in the granulocytes.

Wilson's disease: A Clinical autopsy case report with review of literature.

Wilson's disease is an autosomal recessive disease resulting in defective copper metabolism, which is usually seen in young adults, predominantly affecting liver and brain. Although it is not uncommon in India, variation in epidemiology, clinical presentation and course are reported. However, community-based incidence and prevalence rates are not available in India and incidences are limited to hospital based reports. Most often, the diagnosis is delayed. We present a clinical autopsy case in a 39 year-old female who had presented with clinical symptoms at 18 years of age. The duration of illness was 21 years. Patient's parent had consanguineous marriage and the younger sibling had died at 5 years of age with similar complaints.