MedGen

PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems. [from GeneReviews]

PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems. [from GeneReviews]

Any retinitis pigmentosa in which the cause of the disease is a mutation in the BBS2 gene. [from MONDO]

Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the MSRB3 gene. [from MONDO]

PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems. [from GeneReviews]

Spastic paraplegia-74 (SPG74) is an autosomal recessive neurologic disorder characterized by onset of slowly progressive lower limb spasticity, optic atrophy, and peripheral neuropathy in the first decade (summary by Lossos et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800). [from OMIM]

MRT74 is characterized by intellectual impairment, macrocephaly, and dysmorphic features. Epilepsy with eyelid myoclonus has also been reported (Almuriekhi et al., 2015; Mastrangelo et al., 2020). [from OMIM]

Developmental and epileptic encephalopathy-74 (DEE74) is neurologic disorder characterized by the onset of refractory seizures in the first months of life. Seizure types are variable and include infantile spasms, myoclonic, tonic, atonic, and absence, often with secondary generalization. Affected individuals have severe global developmental delay with hypotonia, severe motor impairment, roving eye movements, and absent language (summary by Shen et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems. [from GeneReviews]

Immunodeficiency-74 (IMD74) is an X-linked recessive specific immunologic disorder characterized by the development of severe respiratory insufficiency in response to infection with the COVID-19 coronavirus, also known as SARS-CoV-2 ssRNA coronavirus. Affected individuals usually require mechanical ventilation in the ICU in order to survive. Laboratory studies show activation of the immune response and may show perturbation of some values, such as increased D-dimers and fibrinogen. In vitro functional studies of patient immune cells show impaired signaling through the TLR7 pathway, resulting in defective type I and type II interferon (IFN) responses. The patients reported to date did not have a history of immunodeficiency or chronic disease (summary by van Der Made et al., 2020). [from OMIM]

Autosomal dominant deafness-74 (DFNA74) is characterized by nonsyndromic postlingual progressive hearing loss, with onset in the third decade of life in most affected individuals (Wang et al., 2018). [from OMIM]

Spermatogenic failure-74 (SPGF74) is characterized by nonobstructive azoospermia and male infertility due to complete meiotic arrest at the spermatocyte zygotene or pachytene stage. Some men exhibit reduced testicular volume and/or reduced testosterone level (Wyrwoll et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150). [from OMIM]

Autosomal dominant intellectual developmental disorder-74 (MRD74) is characterized by global developmental delay, including delay of gross and fine motor skills and speech delay, and variable subtle dysmorphic facial features (Niggl et al., 2023). [from OMIM]

Auriculocondylar syndrome-1 (ARCND1) is an autosomal dominant disorder of the first and second pharyngeal arches and is characterized by malformed ears (question mark ears), prominent cheeks, microstomia, abnormal temporomandibular joint, and mandibular condyle hypoplasia (summary by Masotti et al., 2008). Genetic Heterogeneity of Auriculocondylar Syndrome See also ARCND2A (614669) and ARCND2B (620458), caused by heterozygous or biallelic mutation, respectively, in the PLCB4 gene (600810) on chromosome 20p12; ARCND3 (615706), caused by mutation in the EDN1 gene (131240) on chromosome 6p24; and ARCND4 (620457), caused by mutation the HDAC9 gene (606543) on chromosome 7p21. See also 612798 for isolated question mark ears. Reviews Kokitsu-Nakata et al. (2012) tabulated clinical findings in 24 reported cases of auriculocondylar syndrome. The most common clinical signs observed were ear constriction (100%), abnormal temporomandibular joint (100%), mandibular condyle abnormality (93%), malocclusion (93%), round face (78%), microstomia (78%), micrognathia (78%), prominent cheeks (74%), hearing loss (56%), abnormal palate (55%), and crowded teeth (50%). The authors noted that the phenotype was highly variable in severity, even within families. Liu et al. (2021) reviewed 19 published cases of ARCND1 and tabulated the common features, including micrognathia (79%), auricular malformation (68%), microstomia (67%), prominent cheeks (63%), mandibular hypoplasia (58%), and round face (58%). Asymmetry of mandibular and auricular malformations was present in 4 patients, and the lesions were either more severe on the right or only the right side was affected, suggesting a predilection for right-sided deformities. The authors also noted that severe cases mostly occurred in female patients. Prenatal findings were available in 3 patients, and all showed polyhydramnios, with 2 having micrognathia evident on ultrasonography. The authors suggested that severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios might be prenatal indicators of ARCND. Using a standardized questionnaire sent to referring physicians, Vegas et al. (2022) collected clinical data on 39 patients from 27 families with auriculocondylar syndrome and mutation in the GNAI3, PLCB4, or EDN1 genes. PLCB4 was the most common gene associated with ARCND, being mutated in 16 (59%) of the 27 families. Incomplete penetrance and/or variable expression was observed within families. [from OMIM]