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Introduction In this register-based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age-related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms. Material and methods We followed a nationwide cohort of 542 375 singleton-pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register. Results We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age-related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. Conclusion This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter., Introduction: In this register-based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age-related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms. Material and methods: We followed a nationwide cohort of 542 375 singleton-pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register. Results: We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age-related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. Conclusion: This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter.

Background: Guidelines from the European Hereditary Tumor Group as well as The Danish National Guidelines for Peutz–Jeghers Syndrome (PJS) state that both prenatal diagnosis and preimplantation genetic testing for monogenic disorders (PGT-M) should be offered to patients with PJS. However, only a few cases resulting in viable pregnancies have been published. Objective: We present two cases of PJS patients going through PGT-M for PJS. We highlight the awareness of this possibility and discuss the technical and ethical challenges of performing PGT-M for PJS. Methods and results: Case 1: A 36-year-old male with PJS and his partner were referred for genetic counseling. The patient carried a pathogenic de novo variant in STK11. After a terminated pregnancy of a fetus carrying the same pathogenic variant, microsatellite polymorphic marker analysis was established, and the patient was offered PGT-M. The female partner of the patient gave birth to a healthy boy after five years of fertility treatment. Case 2: A 35-year-old female with PJS and her partner were referred for genetic counseling. She carried an inherited pathogenic STK11 variant. The couple was offered PGT-M. Genetic testing of the embryos was performed using microsatellite polymorphic markers. After two rounds of oocyte extraction a blastocyst predicted not to be affected by PJS was identified. The blastocyst was transferred; however, this did not result in a viable pregnancy. Conclusions: PGT-M can be offered to patients with PJS. The process may be long and filled with ethical dilemmas requiring patients to be motivated and persistent.

PURPOSE: To describe the causes of ectopia lentis (EL) and the outcomes after surgery in a Danish population. SETTING: The Eye Clinic Rigshospitalet and Kennedy Center in Copenhagen. DESIGN: Retrospective cohort study. METHODS: Medical records of patients with nontraumatic EL born after 1980 and seen at the Eye Clinic Rigshospitalet and Kennedy Center from 1983 to 2019 were reviewed. Clinical information regarding family history, comorbidities, genetic workup, ophthalmological examinations, and surgical history was retrieved. RESULTS: 72 patients (38 males), of whom 68 had bilateral EL (94.4%) were identified. Marfan syndrome (MFS) was found in 34 (47.2%) and biallelic variants in ADAMTSL4 in 4 (5.6%). Surgery was performed in 38 (52.8%) patients, 66 eyes, with a median age at the time of first eye surgery of 8.4 years (range 0.8 to 39.0 years) and a follow-up of 2.3 years (range 0 to 25.7 years). Intraocular lenses were implanted in 9 (23.7%) (11 eyes). Corrected distance visual acuity improved from 0.7 to 0.2 logMAR (median) in right eyes and from 0.7 to 0.3 logMAR in left eyes postoperatively. 21 patients (56.8%), 42 eyes, did not experience any surgery-related complications. 3 patients (3 eyes) experienced a perioperative tear in the posterior capsule. Temporary postoperative ocular hypertension was reported in 3 patients (7.9%) (3 eyes), and 2 patients (5.4%) (2 eyes) developed persistent ocular hypertension. There were no cases of postoperative retinal detachment. CONCLUSIONS: The main reason for EL was MFS. Surgery improved visual acuity, and postoperative ocular hypertension was the most common complication, whereas retinal detachment was not observed.

Information regarding hereditary disease predisposition is generally inaccessible for adoptees. The lack of family history restricts access to various surveillance programmes and the overall health of the adoptee. Genetic screening of asymptomatic adoptees could be a compensational tool. However, variant classification is difficult, even more so in certain ethnic groups and in cases where there is no knowledge of family history, as summarised in this review. The usefulness of genetic screening of asymptomatic adoptees is still unknown and requires further research for clarification.

Risk of genetic diseases with autosomal recessive or X-linked inheritance can be unknown to prospective parents until an affected child is born. New technology has enabled carrier screening for hundreds of genetic diseases (expanded carrier screening, ECS). I Denmark, each year estimated 100-180 children are born affected with a serious condition which could have been detected with ECS of the parents. This review describes the considerations and perspectives of a systematic genetic screening programme for prospective parents in the Danish healthcare system.

Direct to consumer genetic testing (DTC-GT) is offered by commercial companies, but the use in the general population has only been sparsely investigated. A questionnaire was sent to 2013 representative Danish citizens asking about their awareness and use of DTC-GT. Individuals who had undergone a genetic test were interviewed to determine if the results had been understood correctly. A pilot study with 2469 questionnaires was performed before this study. In total, 45.4% of the individuals (n = 913/2013) had knowledge about DTC-GT and 2.5% (n = (18 + 5)/913) previously had a genetic test by a private company and 5.8% through the public health care system (n = (48 + 5)/913). Curiosity about own genetic information was the most frequent motivation (40.9%, n = 9/22) as well as knowledge of ancestry (36.4%, n = 8/22) and advice about lifestyle, exercise, or diet (36.4%, n = 8/22). Test of own disease risk was given as a reason in 27.3% (n = 6/22) and seeking possible explanation of specific symptoms in 13.6% (n = 3/22). 50% (n = 11/22) answered that they had become concerned after the test, and 17.4% (n = 4/23) had consulted their GP. Interviews in a subset of respondents from the pilot study revealed problems with understanding the results. One problem was how to interpret the genetic test results with respect to individual risk for a disease. For example, the difference between disease causing genetic variants in monogenetic diseases versus statistical risks by SNPs in multifactorial diseases was not understood by the respondents.

Background: Establishing eye contact between infants and parents is important for early parent-child bonding and lack of eye contact may be a sign of severe underlying disease. The aim of the study was to evaluate the causes of poor or lacking eye contact in infants. Methods: Cross-sectional study reviewing all referrals of infants ≤1 year of age from January 1rst, 2016 to December 31rst, 2018. Medical information was retrieved from patient files covering pregnancy, birth, diagnostic work-up and ocular parameters such as refraction, visual acuity and structural findings. Results: We identified 99 infants with poor or lacking eye contact. The relative frequency of causes was neurologic disease 36.4% (36/99), delayed visual maturation 24.2% (24/99), ocular disease 21.2% (21/99) and idiopathic infantile nystagmus 4.0% (4/99). Fourteen infants had a visual function within age-related norms at first examination despite poor eye contact at the time of referral. Of the infants with available data, 18/27 (33.3%) with neurologic cause, 15/23 (65.2%) with delayed visual maturation and 9/21 (42.9%) with ocular cause had visual acuity within the age-related norm at latest follow-up (0-41 months). In 23 infants, a genetic cause was found. Conclusion: Poor eye contact in infants may be a sign of severe underlying disease, such as neurological or ocular disease. Close collaboration between pediatric ophthalmologists and neuro-pediatricians are warranted in the management of these infants.

Purpose: Bilateral childhood cataracts can be caused by a metabolic disease, constitute a part of a syndrome, run in families, be sporadic or iatrogenic. The amount of work-up needed to establish a cause is discussed and the aim of the present study was to evaluate causes of bilateral childhood cataract. Methods: Chart review of 211 Danish children with bilateral cataracts. Information on work-up was retrieved with special focus on general health, metabolic screening, evaluation for congenital infections and genetic testing. Results: Cataract was seen in combination with systemic disease in 40.8%, 29.4% had hereditary cataracts, 27.0% had isolated cataract, in 1.4% it was associated with ocular malformations and 1.4% had been born prematurely without any other sequelae than the cataract. A genetic cause could be demonstrated in 74 children. Conclusion: Systemic comorbidities are very common in children with cataract and are not always known prior to the diagnosis of cataract. Genetic evaluation, especially targeted analyses, provided a molecular genetic diagnosis in a large proportion of those tested but it also failed to provide a molecular genetic diagnosis in some patients with a family history suggesting autosomal dominant inheritance. Most importantly, in some patients, genetic work-up provided a diagnosis in patients where it had therapeutic consequences and where the systemic disease would have caused irreversible damage, had it not been treated timely. Given the high prevalence of systemic disease, it seems advisable to co-manage children with bilateral cataracts with a pediatrician and to include genetic evaluation as part of the work-up.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting: This was a multicenter retrospective study using information collected from 3 predominant centers. Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

PURPOSE: The aim of this study was to provide a population-based estimate on the prevalence of infantile nystagmus and to describe the causes in the Capital Region of Denmark.METHODS: Review of medical records of children with infantile nystagmus born in the period 1 January 2010 through 31 December 2017 and living in the Capital Region of Denmark. We used birth registry data from Statistics Denmark and the National Danish Birth Registry to calculate the prevalence of nystagmus in children born at term and prematurely.RESULTS: A total of 103 patients (52 males/51 females) with infantile nystagmus were included. The overall prevalence of infantile nystagmus was 6.1 per 10 000 live births. It was higher in premature children (28.4/10 000 live births) than children born at term (4.4/10 000), p < 0.0001, and highest in children born extremely preterm, (97.3/10 000). The most common cause of infantile nystagmus was ocular disease (44%) followed by idiopathic nystagmus (32%), neurological disorders and genetic syndromes (20%) and prematurity without retinopathy of prematurity as the only cause (4%).CONCLUSIONS: In this study, we provide the prevalence of infantile nystagmus based on national medical records in which all residents are accounted for. Our findings show a prevalence of 6.1 per 10 000 live births but six times higher among children born preterm than born at term. Ocular disease was the leading cause of infantile nystagmus with albinism and ocular malformations as the most frequent. In 1/3 of patients, no cause could be identified.

PURPOSE: This study aims to quantify the occurrence of the congenital eye malformations anophthalmia (AO), microphthalmia (MO) and coloboma among liveborn infants in Denmark, and to estimate the rate of chromosomal abnormalities in this group of patients.METHODS: A cohort of patients born in 1995-2012 with diagnoses of MO/AO or coloboma was identified from the Danish National Patient Registry (DNPR), and their ocular and extra-ocular diagnoses were reviewed. In order to assess the occurrence of chromosomal abnormalities in the cohort, the data were cross-referenced with the Danish Cytogenetic Central Registry (DCCR).RESULTS: We identified 415 patients with MO/AO/coloboma in the DNPR. The total number of live births from 1995-2012 was 1,174,299, and the average birth prevalence of MO/AO/coloboma was 3.6/10,000 live births and of MO/AO was 1.2/10,000 live births. Extra-ocular abnormalities were observed in 32.1% of MO/AO cases and 21.7% of coloboma cases. Chromosome analysis was performed in 36.1% of the cohort, and 14.7% of cases had an abnormal karyotype. In 8.7% of the cohort, a chromosome microarray analysis was performed, and in 44.4% of cases, a possibly pathogenic copy number variation was observed.CONCLUSION: The birth prevalence of MO/AO/coloboma in Denmark has been steady at 3.6/10,000 live births during the last 17 years. The rate of syndromic cases was lower compared to other studies. A relatively high rate of pathogenic chromosomal aberrations was observed, suggesting an important role for cytogenetic analysis in this group of patients.

The hypotone neonate, floppy infant, often proves to be a diagnostic challenge, as the causes of floppy infant syndrome are many and often rare. In this case story a floppy girl was diagnosed with the rare, autosomal recessive disease pontocerebellar hypoplasia type I. The tests for the most common causes of floppy infant syndrome showed nothing abnormal, but an array comparative genomic hybridization test gave information of loss of heterozygosity. This helped to narrow the list of plausible diagnoses and eventually led to the diagnosis of pontocerebellar hypoplasia type I.

BACKGROUND: Cornea plana (CNA) is a hereditary congenital abnormality of the cornea characterized by reduced corneal curvature, extreme hypermetropia, corneal clouding and hazy corneal limbus. The recessive form, CNA2, is associated with homozygous or compound heterozygous mutations of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described.CASE PRESENTATION: In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation is predicted to destabilize the structure of keratocan, leading to the classical ocular phenotype in the affected individuals. All the four known missense mutations, including the variation found in this family, affect the conserved residues of the leucine rich repeat domain of keratocan. These mutations are predicted to result in destabilization of the protein.CONCLUSION: We present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function, and this knowledge will ease the interpretation of future findings of mutations in these areas in other families with cornea plana.

Background: Cornea plana (CNA) is a hereditary congenital abnormality of the cornea characterized by reduced corneal curvature, extreme hypermetropia, corneal clouding and hazy corneal limbus. The recessive form, CNA2, is associated with homozygous or compound heterozygous mutations of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described. Case presentation: In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation is predicted to destabilize the structure of keratocan, leading to the classical ocular phenotype in the affected individuals. All the four known missense mutations, including the variation found in this family, affect the conserved residues of the leucine rich repeat domain of keratocan. These mutations are predicted to result in destabilization of the protein. Conclusion: We present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function, and this knowledge will ease the interpretation of future findings of mutations in these areas in other families with cornea plana.

Anophthalmia and microphthalmia (AO/MO) are rare congenital eye malformations, in which the eyeball is apparently absent or smaller than normal, which causes various degrees of visual impairment. Over 200 different AO/MO-related syndromes have been described, but the genetic background is unknown in many cases. The aim of this article is to give an overview of AO/MO, focusing on the genetic background. It is illustrated that the future identification of new AO/MO related genes will benefit in the genetic counseling of AO/MO patients, and in the understanding of eye development and congenital eye malformations.