Surgical outcomes of a congenital nystagmus family with a missense mutation in the FRMD7 gene.

Background: This study aimed to assess the effectiveness of surgery in the management of vertical compensatory head posture in patients with congenital nystagmus (CN) inherited in an X-linked manner in a Chinese family and determine the molecular pathogenesis of this disease. Methods: We studied 18 members belonging to four generations in a family with congenital nystagmus. Parks shift of neutral zone surgeries were performed on 7 patients with vertical compensatory head posture from the family. In addition, head posture, visual acuity, and stereopsis of the 7 patients were evaluated before and 2-years after the displacement surgeries. Gene alternations of the disease were researched by sequencing a candidate gene (FRMD7). From each generation of the family, one patient (including the proband) and one normal control were sampled for Sanger sequencing. Results: Over a median follow-up period of 2 years, the anomalous head posture, visual acuity, and stereopsis significantly improved postoperatively (P < 0.05). Sanger sequencing revealed that a variant c.586G > T (p.D196Y) in exon 7 of FRMD7 was co-segregated with the disease in this family. Conclusions: Parks shift of neutral zone surgeries relieved the vertical compensatory head posture and improved visual acuity and stereopsis in the primary position of CN patients. In this study, it was concluded that a missense mutation in exon 7 (c.586G > 7, p.D196Y) in FRMD7 was possibly responsible for the disease in this family.

Electroretinography in congenital nystagmus patients with a normal fundus examination.

PURPOSE: To identify the ophthalmic causes of congenital nystagmus with normal eye examination by electroretinography (ERG). STUDY DESIGN: Retrospective observational study. METHODS: We reviewed the medical records of patients younger than 6 months of age who presented between June 2008 and November 2011 with nystagmus and no other neurological signs following an otherwise normal eye examination. A complete ophthalmic examination and ERG (Nicolet Bravo system; Nicolet Biomedial & RETIscan; Roland Instruments), fundus photography, and Ishihara color test were performed to identify any ophthalmic causes of congenital nystagmus. RESULTS: Thirty-three patients met the criteria. Rod dysfunction was diagnosed in 4 patients (12.1%), cone dysfunction in 2 patients (6.1%), and cone-rod dysfunction in 1 patient (3.0%). The results of ERG were negative in 2 patients (6.1%). Idiopathic infantile nystagmus was diagnosed in the remaining 24 patients (72.7%) based on their normal ERG examination. CONCLUSIONS: In Korean congenital nystagmus patients with a normal fundus examination, achromatopsia and Leber's congenital amaurosis are uncommon causes. ERG is needed to make a definite diagnosis and provide prognostic information in congenital idiopathic nystagmus patients with a normal fundus examination.

Truncated FRMD7 proteins in congenital Nystagmus: novel frameshift mutations and proteasomal pathway implications.

Idiopathic congenital nystagmus (ICN) manifests as involuntary and periodic eye movements. To identify the genetic defect associated with X-linked ICN, Whole Exome Sequencing (WES) was conducted in two affected families. We identified two frameshift mutations in FRMD7, c.1492dupT/p.(Y498Lfs*15) and c.1616delG/p.(R539Kfs*2). Plasmids harboring the mutated genes and qPCR analysis revealed mRNA stability, evading degradation via the NMD pathway, and corroborated truncated protein production via Western-blot analysis. Notably, both truncated proteins were degraded through the proteasomal (ubiquitination) pathway, suggesting potential therapeutic avenues targeting this pathway for similar mutations. Moreover, we conducted a comprehensive analysis, summarizing 140 mutations within the FRMD7 gene. Our findings highlight the FERM and FA structural domains as mutation-prone regions. Interestingly, exons 9 and 12 are the most mutated regions, but 90% (28/31) mutations in exon 9 are missense while 84% (21/25) mutations in exon 12 are frameshift. A predominant occurrence of shift code mutations was observed in exons 11 and 12, possibly associated with the localization of premature termination codons (PTCs), leading to the generation of deleterious truncated proteins. Additionally, our conjecture suggests that the loss of FRMD7 protein function might not solely drive pathology; rather, the emergence of aberrant protein function could be pivotal in nystagmus etiology. We propose a dependence of FRMD7 protein normal function primarily on its anterior domain. Future investigations are warranted to validate this hypothesis.

A common cause for nystagmus in different congenital stationary night blindness mouse models.

In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e. nystagmus. Given the specific expression of mGluR6 and Cav 1.4 in the photoreceptor to bipolar cell synapses, as well as their clinical association with CSNB, we hypothesize that Grm6nob3 and Cav 1.4-KO mutants show, like the Nyxnob mouse, oscillations in both their RGC activity and eye movements. Using multi-electrode array recordings of RGCs and measurements of the eye movements, we demonstrate that Grm6nob3 and Cav 1.4-KO mice also show oscillations of their RGCs as well as a nystagmus. Interestingly, the preferred frequencies of RGC activity as well as the eye movement oscillations of the Grm6nob3 , Cav 1.4-KO and Nyxnob mice differ among mutants, but the neuronal activity and eye movement behaviour within a strain remain aligned in the same frequency domain. Model simulations indicate that mutations affecting the photoreceptor-bipolar cell synapse can form a common cause of the nystagmus of CSNB by driving oscillations in RGCs via AII amacrine cells. KEY POINTS: In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), their oscillatory eye movements (i.e. nystagmus) are caused by synchronous oscillating retinal ganglion cells. Here we show that the same mechanism applies for two other CSNB mouse models - Grm6nob3 and Cav 1.4-KO mice. We propose that the retinal ganglion cell oscillations originate in the AII amacrine cells. Model simulations show that by only changing the input to ON-bipolar cells, all phenotypical differences between the various genetic mouse models can be reproduced.

Micro chromosomal deletions at the NYS7 locus and autosomal dominant nystagmus.

Nystagmus is an ocular condition characterized by bilateral involuntary ocular oscillation which can severely affect vision. When not associated with other ocular or systemic diseases, it is referred to as idiopathic or congenital motor nystagmus (CMN). Genome-wide linkage studies have previously identified several loci associated with CMN, however the genes responsible for some of these loci have yet to be identified. We have examined a large, five-generation family with autosomal dominant CMN. Our purpose was to characterize the clinical manifestations and reveal the molecular basis of the disease in this family. In addition to full ophthalmic examination and imaging, molecular analysis included copy number variation analysis, linkage studies, and Sanger sequencing. Expression analyses of candidate genes was done by real-time PCR. Of the 68 family members, 27 subjects in five-generations had CMN, in line with an autosomal dominant inheritance pattern. Molecular analysis was performed on 27 members, 15 of them affected by CMN. Copy number variation analysis using array comparative genomic hybridization (aCGH) revealed a novel deletion located on 1q32 (NYS7) among affected individuals. Linkage analysis using polymorphic markers demonstrated full segregation with a heterozygous haplotype in all affected patients, with a LOD score of >5. Sanger sequencing of affected subjects revealed a novel deletion of 732,526 bp in the linkage interval. No protein-coding genes exist within the deleted region; however, the deletion disrupts topologically associated domains encompassing the gene NR5A2 and the non-protein coding MIR181A. Both are strongly associated with other genes expressed in the retina such as PROX1, which in turn is also associated with genes related to nystagmus such as PAX6. We therefore hypothesized that the deletion might affect NR5A2 and MIR181A expression, causing CMN. Expression analysis by real-time PCR showed significantly lower expression of NR5A2, and significantly higher expression of PROX1 among patients compared with controls. To conclude, among a large five-generation family with autosomal dominant CMN, a large deletion in the interval of NYS7 was linked with the disease. No protein-coding genes exist inside the deleted region, and so the exact mechanism in which CMN is caused is uncertain. Based on topological association and expression analyses we suggest a possible mechanism for the pathogenesis.

FRMD7 Gene Alterations in a Pakistani Family Associated with Congenital Idiopathic Nystagmus.

Congenital idiopathic nystagmus (CIN) is an oculomotor disorder characterized by repetitive and rapid involuntary movement of the eye that usually develops in the first six months after birth. Unlike other forms of nystagmus, CIN is widely associated with mutations in the FRMD7 gene. This study involves the molecular genetic analysis of a consanguineous Pakistani family with individuals suffering from CIN to undermine any potential pathogenic mutations. Blood samples were taken from affected and normal individuals of the family. Genomic DNA was extracted using an in-organic method. Whole Exome Sequencing (WES) and analysis were performed to find any mutations in the causative gene. To validate the existence and co-segregation of the FRMD7 gene variant found using WES, sanger sequencing was also carried out using primers that targeted all of the FRMD7 coding exons. Additionally, the pathogenicity of the identified variant was assessed using different bioinformatic tools. The WES results identified a novel nonsense mutation in the FRMD7 (c.443T>A; p. Leu148 *) gene in affected individuals from the Pakistani family, with CIN resulting in a premature termination codon, further resulting in the formation of a destabilized protein structure that was incomplete. Co-segregation analysis revealed that affected males are hemizygous for the mutated allele c.443T>A; p. Leu148 * and the affected mother is heterozygous. Overall, such molecular genetic studies expand our current knowledge of the mutations associated with the FRMD7 gene in Pakistani families with CIN and significantly enhance our understanding of the molecular mechanisms involved in genetic disorders.

Alteration of Degree Centrality in Adolescents With Early Blindness.

Congenital nystagmus in infants and young children can lead to early blindness (EB). Previous neuroimaging studies have demonstrated that EB is accompanied by alterations in brain structure and function. However, the effects of visual impairment and critical developmental periods on brain functional connectivity at rest have been unclear. Here, we used the voxel-wise degree centrality (DC) method to explore the underlying functional network brain activity in adolescents with EB. Twenty-one patients with EBs and 21 sighted controls (SCs) underwent magnetic resonance imaging. Differences between the two groups were assessed using the DC method. Moreover, the support vector machine (SVM) method was used to differentiate patients with EB patients from the SCs according to DC values. Compared with the SCs, the patients with EB had increased DC values in the bilateral cerebellum_6, cerebellum vermis_4_5, bilateral supplementary motor areas (SMA), and left fusiform gyrus; the patients with EB had decreased DC values in the bilateral rectal gyrus and left medial orbital frontal gyrus. The SVM classification of the DC values achieved an overall accuracy of 70.45% and an area under the curve of 0.86 in distinguishing between the patients with EB and the SCs. Our study may reveal the neuromechanism of neuroplasticity in EB; the findings provide an imaging basis for future development of restorative visual therapies and sensory substitution devices, and future assessments of visual rehabilitation efficacy.

Receptive Field Sizes of Nyxnob Mouse Retinal Ganglion Cells.

Patients with congenital nystagmus, involuntary eye movements, often have a reduced visual acuity. Some of these patients have a retinal-specific mutation in the protein nyctalopin, which is also present in the Nyxnob mouse. In these mice, retinal ganglion cells (RGCs) have oscillatory activity, which leads to expanded axonal projections towards the dLGN and consequently to a desegregation of retinal projections to the brain. In this study, we investigate whether the receptive fields of Nyxnob RGCs have also expanded by measuring the size of their receptive fields using MEA recordings. Contrary to our expectation, relative to wild-type (WT) mice we found receptive field sizes in the Nyxnob retina had not increased but instead had decreased for green-light preferring RGCs. Additionally, we also found the receptive fields of UV-light preferring RGCs are larger than green-light preferring RGCs in both WT and Nyxnob mice.

X-linked FRMD7 gene mutation in idiopathic congenital nystagmus and its role in eye movement: A case report and literature review.

Background: Idiopathic congenital nystagmus (ICN) is an inherited disorder characterized by uncontrollable binocular conjugating oscillation. X-linked idiopathic congenital nystagmus is one of the most prevalent types of ICN. Elucidation of the genetic mechanisms involved in ICN will enhance our understanding of its molecular etiology. Case presentation: We report a girl with uncontrollable binocular oscillation and anomalous head posture, then presented a novel heterozygous missense variant (c.686G>T) within the mutation-rich region of the FERM domain containing 7 (FRMD7) gene in her family member. The girl received occlusion therapy and surgical operation which balanced her binocular vision and corrected the anomalous head posture. Conclusions: This is the first report on a mutation (c.686G>T) caused the substitution of Arg (R) with Leu (L) at position 229 (p.R229L) of the FRMD7 protein in a patient with ICN.

Vestibular Function Measured Using the Video Head Impulse Test in Congenital Nystagmus and Vertigo: A Case Report.

In patients with congenital nystagmus (CN), the study of vestibular function is complicated by many factors related to the measurement of the vestibulo-ocular reflex (VOR) by means of caloric testing and the video head impulse test (vHIT), and to date no such studies have successfully employed the vHIT to evaluate vestibular function in these patients. We present a case with CN and vertigo in which peripheral vestibular function was evaluated using the vHIT system, including head impulse testing and the suppression head impulse protocol. We show that it is possible (a) to identify lateral VOR changes such as abnormalities resembling those produced by bilateral vestibular lesions, though not necessarily related to the same mechanism; (b) to identify peripheral VOR lesions of the vertical semicircular canals (SCC); and (c) to document compensation and recovery subsequent to these peripheral lesions during follow-up of patients with CN. vHIT is a useful tool that should be used to study vestibular function in patients with CN and vertigo, which could constitute a new clinical application of this technique.

Genotype-Phenotype Analysis and Mutation Spectrum in a Cohort of Chinese Patients With Congenital Nystagmus.

Purpose: Congenital nystagmus (CN) is a genetically and clinically heterogeneous ocular disorder that manifests as involuntary, periodic oscillations of the eyes. To date, only FRMD7 and GPR143 have been reported to be responsible for causing CN. Here, we aimed to identify the disease-causing mutations and describe the clinical features in the affected members in our study. Methods: All the subjects underwent a detailed ophthalmic examination. Direct sequencing of all coding exons and splice site regions in FRMD7 and GPR143 and a mutation assessment were performed in each patient. Results: We found 14 mutations in 14/37 (37.8%) probands, including nine mutations in the FRMD7 gene and five mutations in the GPR143 gene, seven of which are novel, including c.284G>A(R95K), c.964C>T(P322S), c.284+10T>G, c.901T>C (Y301H), and c.2014_2023delTCACCCATGG(S672Pfs*12) in FRMD7, and c.250+1G>C, and c.485G>A (W162*) in GPR143. The mutation detection rate was 87.5% (7/8) of familial vs. 24.1% (7/29) of sporadic cases. Ten mutations in 24 (41.7%) non-syndromic subjects and 4 mutations in 13(30.8%) syndromic subjects were detected. A total of 77.8% (7/9) of mutations in FRMD7 were concentrated within the FERM and FA domains, while all mutations in GPR143 were located in exons 1, 2, 4 and 6. We observed that visual acuity tended to be worse in the GPR143 group than in the FRMD7 group, and no obvious difference in other clinical manifestations was found through comparisons in different groups of patients. Conclusions: This study identified 14 mutations (seven novel and seven known) in eight familial and 29 sporadic patients with congenital nystagmus, expanding the mutational spectrum and validating FRMD7 and GPR143 as mutation hotspots. These findings also revealed a significant difference in the screening rate between different groups of participants, providing new insights for the strategy of genetic screening and early clinical diagnosis of CN.

p.His16Arg of STXBP1 (MUNC18-1) Associated With Syntaxin 3B Causes Autosomal Dominant Congenital Nystagmus.

Congenital nystagmus (CN) is an ocular movement disorder manifested as involuntary conjugated binocular oscillation and usually occurs in early infancy. The pathological mechanism underlying CN is still poorly understood. We mapped a novel genetic locus 9q33.1-q34.2 in a larger Chinese family with autosomal dominant CN and identified a variant (c.47A>G/p.His16Arg) of STXBP1 by exome sequencing, which fully co-segregated with the nystagmus phenotype in this family and was absent in 571 healthy unrelated individuals. The STXBP1 encodes syntaxin binding protein 1 (also known as MUNC18-1), which plays a pivotal role in neurotransmitter release. In unc-18 (nematode homolog of MUNC18-1) null Caenorhabditis elegans, we found that the p.His16Arg exhibits a compromised ability to rescue the locomotion defect and aldicarb sensitivity, indicating a functional defect in neurotransmitter release. In addition, we also found an enhanced binding of the p.His16Arg mutant to syntaxin 3B, which is a homolog of syntaxin 1A and specifically located in retinal ribbon synapses. We hypothesize that the variant p.His16Arg of STXBP1 is likely to affect neurotransmitter release in the retina, which may be the underlying etiology of CN in this family. Our results provide a new perspective on understanding the molecular mechanism of CN.

Congenital Nystagmus and Its Congeners.

In recent years, we have made enormous strides in elucidating the phenomenology of congenital nystagmus. The purpose of this review is to briefly summarize our current understanding of congenital nystagmus in terms of its clinical symptomatology, pathophysiology, differential diagnosis, and ancillary testing, and clinical management. Finally, this discussion provides the reader with an armamentarium of clinical pearls to facilitate diagnosis of the numerous sensory visual disorders that can underlie congenital nystagmus.

Consecutive strabismus after infantile nystagmus syndrome surgery and potential risk factors.

PURPOSE: The aim of this study is to evaluate the incidence of consecutive strabismus after infantile nystagmus surgery and its potential risk factors. METHODS: A retrospective study including 89 patients was conducted. Patients presented infantile nystagmus (idiopathic or ocular disease-associated nystagmus) without previous or coincidental strabismus. Sex, age at surgery, amblyopia, botulinum toxin (BT) injection before surgery, spherical equivalent, anisometropia, surgery procedure (Anderson's or retroequatorial recessions of four horizontal recti), and follow-up were analyzed. Kaplan-Meier and univariate Cox regression were performed. RESULTS: The median age at surgery was 5 years. The median follow-up was 36 months. The incidence of consecutive strabismus was 11.2%. There were eight patients with exotropia and two patients with esotropia. Consecutive strabismus was associated with severe bilateral amblyopia (p = 0.036), previous treatment with BT injection (p = 0.025), and large recessions of the four horizontal muscles (p = 0.001). The hazard ratio for patients with severe bilateral amblyopia was 5.4 (95% CI 1.1-25.8), and for patients previously treated with BT was 6.1 (1.3-29.3). The survival rate was 95.4% at 6 months and 88.5% at 3 years. CONCLUSION: Severe bilateral amblyopia, previous BT treatment, and type of surgery seem to be associated with consecutive strabismus after infantile nystagmus surgery. Most cases appear within the first months after surgery.

Prevalence and causes of infantile nystagmus in a large population-based Danish cohort.

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.

Foveation dynamics in congenital nystagmus IV: vergence.

PURPOSE: To evaluate foveation dynamics and characteristics of vergence eye movements during fixation of static targets at different distances and while tracking a target moving in depth in a subject with congenital nystagmus (CN). METHOD: Eye movements of a well-studied subject with CN were recorded using the magnetic search coil technique and analyzed using the OMtools software, including the eXpanded Nystagmus Acuity Function (NAFX). RESULTS: Both the phase planes and NAFX values during fixation of targets at various near distances were equivalent to those during fixation of a far target. When applied to vergence data, the NAFX values ("binocular" NAFX) were higher than for the individual eye data. Vergence tracking of targets moving in depth was demonstrated and was accurate for targets moving at speeds up to ~ 35°/sec. CONCLUSIONS: Target foveation qualities during fixation of targets at various near distances were equivalent to that during fixation of a far target. Stereo discrimination was limited by the foveation quality of the eye with the higher NAFX waveform. Foveation period slopes during vergence tracking demonstrated vergence movements despite the ongoing CN oscillation. Similar to what we found with fixation, pursuit, and the vestibulo-ocular systems, these findings establish that vergence in both static and dynamic viewing conditions functions normally in the presence of the CN oscillation.

Nystagmus-related FRMD7 gene influences the maturation and complexities of neuronal processes in human neurons.

AIMS: Idiopathic congenital nystagmus (ICN) is an oculomotor disorder caused by the defects in the ocular motor control regions of the brain. Mutations in FRMD7, a member of the FERM family of proteins, associated with cytoskeletal dynamics, are the most frequent causes of X-linked ICN. Previous studies illustrated that FRMD7 is involved in the elongation of neurites during neuronal development; however, almost all the studies were performed on mice cell models. The complexity in the human neuronal network might suggest a unique vulnerability of human neurons to FRMD7 mutations. METHODS: Herein, we successfully established human neuronal cell models with FRMD7 mutations, from fibroblasts-reprogrammed neurons (iNs). In these neurons, the complexity of the neuronal processes was measured by the induced ratio, total neurite length, the number of terminals, and the number of maturation neurons. RESULTS: The complexity of the neuronal processes was greatly reduced during various reprogramming stages in the presence of FRMD7 mutations. Consistently, the expression of the three main Rho GTPases was significantly increased by FRMD7 mutations. Interestingly, a slightly diverse phenotype is observed in different derived neurons. CONCLUSION: We established ideal human neuron models and confirmed that the mutation in FRMD7 influences the maturation and complexities of neuronal processes, which might be involved with the Rho GTPase signaling.

Clinical and molecular findings of FRMD7 related congenital nystagmus as adifferential diagnosis of ocular albinism.

BACKGROUND: Congenital nystagmus is one of the most common neuro-ophthalmological disorders. X chromosome-linked forms are associated with pathogenic variants of the GPR143 and FRMD7 genes. MATERIALS AND METHODS: Patients' DNA was analyzed using a next-generation sequencing (NGS) panel of genes involved in albinism and related pathologies (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, C10ORF11, GPR143, SLC38A8, HPS 1 to 10, LYST, MITF, FRMD7) Results: We report a 4 generation family with 5 affected members initially referred for molecular diagnosis of ocular albinism. A missense variant of FRMD7 was found in 3 affected cases and one female carrier. We show that the disease in the affected girl is due to skewed inactivation of the X chromosome. CONCLUSIONS: By compiling all the published cases we discuss the variable penetrance among females due to different types of mutation and to X-inactivation.

X-linked inheritances recessive of congenital nystagmus and autosomal dominant inheritances of congenital cataracts coexist in a Chinese family: a case report and literature review.

BACKGROUND: Congenital nystagmus (CN) and congenital cataracts are distinct eye diseases and are usually isolated. Cases with CN and congenital cataracts caused by different genes in one family have been rarely reported. CASE PRESENTATION: A 27-year-old man presented with CN and congenital cataracts and he underwent cataract extraction 2 weeks after birth. Three years later, he had posterior chamber intraocular lens implantation. The proband's mother was only afflicted by bilateral lens opacities. Lensectomy was performed in both eyes at age 15. The proband's daughter had bilateral central cataracts and no nystagmus. She had undergone cataract extraction when she was two months old. In this family, 8 affected individuals were affected by bilateral cataracts, and three of them presented with CN. The genetic analysis was performed using a specific Hereditary Ophthalmological Disease Gene Panel on proband and his parents (one of which was a patient). PCR and Sanger sequencing verified the presence of these variants in all members of the family. The novel mutation, c.498-3C > T, in FRMD7 explains why X-Linked recessive inheritance of CN was found in a subset of patients. A heterozygous mutation of the GJA8 gene (c.139G > C), was identified in all patients and thus explains the autosomal dominant pattern of inheritance of congenital cataracts within the family. CONCLUSIONS: This is the first time that FRMD7 and GJA8 gene mutations have been linked to the pathogenesis of a family with both CN and congenital cataracts. The phenomenon of two different genetic patterns coexisting in one family is rare.